Aging and the Dendritic Cell System: Implications for Cancer

Abstract

The immune system shows a decline in responsiveness to antigens both with aging, as well as in the presence of tumors. The malfunction of the immune system with age can be attributed to developmental and functional alterations in several cell populations. Previous studies have shown defects in humoral responses and abnormalities in T cell function in aged individuals, but have not distinguished between abnormalities in antigen presentation and intrinsic T cell or B cell defects in aged individuals. Dendritic cells (DC) play a pivotal role in regulating immune responses by presenting antigens to naïve T lymphocytes, modulating Th1/Th2/Treg balance, producing numerous regulatory cytokines and chemokines, and modifying survival of immune effectors. DC are receiving increased attention due to their involvement in the immunobiology of tolerance and autoimmunity, as well as their potential role as biological adjuvants in tumor vaccines. Recent advances in the molecular and cell biology of different DC populations allow for addressing the issue of DC and aging both in rodents and humans. Since DC play a crucial role in initiating and regulating immune responses, it is reasonable to hypothesize that they are directly involved in altered antitumor immunity in aging. However, the results of studies focusing on DC in the elderly are conflicting. The present review summarizes the available human and experimental animal data on quantitative and qualitative alterations of DC in aging and discusses the potential role of the DC system in the increased incidence of cancer in the elderly.

1. Introduction

Immunosenescence refers to the decline in immune function associated with aging in humans and animals [1]. Many diseases observed in the elderly have an immunological basis and are associated with the decline of immune response to exogenous antigens and an increased propensity to autoimmune reactivity. Clinically, the consequences of impaired immune functions in the elderly include an increased susceptibility to infections, malignancies and autoimmunity, as well as diminished responses to vaccination [2, 3]. Both T and B cell immune responses are dramatically affected by aging [4, 5], although age-associated immunological alterations also occur in innate immune cells, affecting both the phenotype and function. Macrophages, neutrophils, natural killer (NK) cells and NKT cells are all affected by aging [6]. However, the gerontologic literature on potential alterations in dendritic cells (DC) associated with aging is scant. Definitive studies on age-related changes in antigen processing remain to be done.

DC have received increasing attention due to their potential use as biological adjuvants in tumor vaccines and their involvement in the immunobiology of tolerance and autoimmunity. DC are known to be the most potent antigen-presenting cells (APC) capable of activating naïve T cells and modulating key immune responses. DC are present in non-lymphoid peripheral tissues where they sample antigens from the environment. Thus, any foreign or tumor antigen(s) that is encountered can become rapidly endocytosed, processed, and presented to T cells resulting in the initiation of antigen-specific immune responses or immune tolerance. In recent years, it has become apparent that there are different subclasses of DC whose interactions with T cells have different outcomes [7]. Formerly called ‘myeloid’ and ‘lymphoid’ DC, DC1 and DC2, or conventional (mDC) and plasmacytoid DC (pDC) subpopulations, respectively, these subsets differentially regulate immunity, tolerance, and Th1/Th2/Treg balance [8, 9]. Follicular DC are not discussed in this review and their alterations in aging have been recently summarized elsewhere [10].

Few groups have addressed the topic of DC and aging [11, 12]. The multifactorial control of aging has been analyzed to some extent to identify the parameters that influence life span and confirm that immune responsiveness is centrally involved in aging. Results from these studies support the hypothesis that age-related immune dysfunction might have an impact on life span. In fact results from studies on centenarians demonstrate that healthy individuals who have reached the extreme limit of human life in a good clinical condition are equipped with well preserved and efficient immune defense mechanisms [13]. Since both pDC and mDC play a crucial role in immune responses, it is conceivable that they also regulate antitumor immunity in aging. However there is little information in this area of research, and we are only now beginning to understand the role of DC dysfunction in cancer [14] and its importance in the regulation of antitumor immune responses [15-17]. However, much remains to be learned about these cells and their functions in tumor immunosurveillance during aging.

2. Animal studies

2.1. Dendritic cell numbers in aged experimental animals

Analysis of the numbers of DC in the dermis (Langerhans cells, LC) was among the first and commonly used methods to compare DC in young and old experimental animals (Table 1). In 1983, Schwartz et al. reported that the number of LC was statistically decreased in the hamster cheek pouch in old animals [18]. Sprecher et al. have demonstrated decreased density and impaired function of epidermal DC populations in aged mice [19]. Similarly, decreased numbers of DC were described in the epidermis and mucosa from aged animals by other groups. For instance, the number of major histocompatibility complex (MHC) class II+ LC in skin from aged (16- to 18-month old) BALB/c mice was approximately 40% lower than that in the skin from young (2- to 3-month old) mice [20]. Choi and Sauder have reported that aged (18 months old) mice have approximately two-thirds the number of LC that young (10−12 weeks old) animals of the same strain did [21]. These data were recently confirmed by Cumberbatch et al. who showed that the frequency of MHC class II+ LC in the epidermis of older (6- month-old) mice was found to be reduced significantly compared with that observed for young (6−8-week-old) mice [22].

Table 1.

Alterations in the DC system in aged mice

DC function	Model	Note	Year	Ref
Age-related changes in autostimulatory activity were not observed in DC	DC were isolated from the lymph nodes as shortly attached cells		1984	[96]
Stimulatory capacity of DC increased with age	Syngeneic MLR	Age-dependent changes in DC properties were not detected in terms of direct plaque-forming response, response to concanavalin A, or in the allogeneic MLR	1986	[43]
Distribution and quantitation of LC in response to infection differed in young and aged mice	LC were assessed in epithelial flat mounts before and after infection with P. aeruginosa topically applied to the scarified cornea		1986	[23]
DC ability to induce T cell proliferation in syngeneic and allogeneic could be decreased, unchanged or increased with age	MLR assay	Age-dependent alterations in the capacity of DC to stimulate syngeneic or allogeneic MLR depended on mouse strain	1986	[42]
LC numbers were decreased in aged mice	Histochemical evaluation of cell numbers	Contact allergy may be diminished in aged mice	1986	[44, 45]
Aged mice had ∼2/3 the number of LC that young animals did	LC density was assessed in epidermal sheets prepared from ear skin of mice and examined by histochemistry	Although the aged animals demonstrated increased variability in the allergic contact sensitivity response to TNCB, there was no overall difference in the cutaneous immunoreactivity between age groups	1987	[21]
The numerical density of LC in old mice was reduced by 30−60 % compared with that in young mice.	LC were analyzed in EDTA-separated epithelial sheets from the cheek, palate mucosa, and ear and footpad skin	The general distribution of LC was unchanged with age, but those in epithelia from the old mice were more varied in shape	1987	[24]
The number of LC was found identical in 1-, 11-, and 22- month-old animals	Counting on suction blister skin biopsies	Skin swelling induced by DNFB sensitization was reduced in 22-month-old mice	1987	[97]
The number of LC in skin from aged mice was 40% lower than in skin from young mice	Histochemical analysis of LC in the skin	Cytokines, particularly IL-3, could reconstitute the number of LC in skin from aged mice and the percentage increment in LC was much higher for skin from aged mice than from young mice	1989	[20]
Decreased density and impaired function of epidermal DC was observed in the elderly	Skin-lymphocyte reaction assay and the ability to stimulate the proliferation of sensitized T cells in the presence of the sensitizing antigen	The capacity of LC to transport antigen from the skin to the draining LN was found in vivo to be comparable to that of young mice	1990	[19]
In the primary MLR, DC from aged SAMP1 mice showed less stimulatory activity than those of age-matched BALB/c or young SAMP1 mice	Substrain of senescence-accelerated mouse (SAMP1) model	Decreases in the stimulatory activity of DC were related to changes in the surface density of MHC class II and ICAM-1, but not B7−1 or B7−2 molecules	1995	[41]
Morphology of DC in the thymus of old mice was altered: the cytoplasm appeared clarified, swollen, and empty as if having lost most of the cellular components	Morphometric analysis of DC		1996	[28]
DC of LN show degenerative characteristics with decreased adhesion molecule expression, less dendrite formation, and reduced antigen trapping capacity	Morphometric evaluation of cells		2001	[46]
The frequency of LC in older mice was reduced. TNF-α induced migration of LC from skin was reduced in older animals, whereas, the percentage of LC that migrated in response to IL-1β was comparable for both young and aged mice.	IHC, Analysis of DC migration in vivo	LC mobilization and the subsequent accumulation of DC in regional LN in response to topical challenge with a chemical allergen were less vigorous in older mice.	2002	[22]
APC from old mice induced similar lymphocyte proliferative responses but lower lymphocyte cytotoxicity and a reduced number of CD8+ T cells producing IFN-γ in comparison with APC from young animals. The in vivo migration of APC was higher in old than in young mice.	APC were obtained by incubating peritoneal monocyte-macrophage cells with GM-CSF (immature APC) or GM-CSF and IFN-γ (mature APC) for 8 days	The low expression of the mRNA for the migratory CCR7 chemokine receptor present in immature APC from old mice was greatly increased in mature APC up to the levels found in APC from young animals.	2002	[48]
The percentage of CD11c+ DC in the bone marrow and spleen and expression of MHC class II and CD86 molecules on DC in old mice were reduced	Athymic nude mice treated with FLT3 ligand	The distribution of CD11c+CD8α+ DC in the lymphoid tissues was not different in young and old mice. Although, FLT3 ligand had a higher inductive potential on the expansion of DC from the bone marrow in the elderly mice, the total level of DC in the young mice was still significantly higher as compared to the old animals.	2004	[39]
DC from aged mice were less capable in T cell activation and their migration to draining lymphoid organs was reduced	Adoptive transfer of T cells and DC in a TCR transgenic model		2005	[98]
Aged mice immunized with DC pulsed with OVA survived significantly shorter after challenge with OVA-expressing tumor cells as compared to equally treated young mice	Murine tumor models and bone marrow-derived DC		2005	[92]
In contrast to young mice, no antitumor or cytotoxic responses were found after old mice were vaccinated with old DC	Evaluation of tumor apoptotic bodies pulsed DC	Co-administration of anti-OX-40 or anti-4−1BB antibodies vigorously enhanced the antitumor immune response in both young and old mice.	2006	[93]
Innate TLR immune priming function of DC is preserved with aging	Allogeneic and infectious murine experimental systems	Both myeloid bone marrow derived and splenic DC were tested.	2006	[99]
DC from old mice were 4 times less effective than were young DC in stimulating syngeneic CD4+ T-cell proliferation. Old DC have decreased DC-SIGN expression, decreased IL-6 and TNF-α and increased IL-10 production.	Analysis of CD11c+CD4−CD8α− DC of old and young C57BL/6 mice	Old DC were less effective in inducing tumor-specific immunity.	2006	[49]

DC, dendritic cells; DC-SIGN, DC-specific/intracellular adhesion molecule type 3-grabbing nonintegrin; DNFB, dinitrofluorobenzene; GM-CSF, granulocyte-macrophage colony-stimulating factor; ICAM-1, intercellular adhesion molecule-1; IHC, immunohistochemistry; LC, Langerhans cells; LN, lymph node; MLR, mixed leukocyte reaction; OVA, ovalbumin; TLR, Toll-like receptors; TNCB, trinitrochlorobenzene.

In the study of Hazlett et al., the morphology, distribution and quantitation of DC were determined in epithelial flat mounts from naturally resistant (Swiss-Webster and CD2F1) 6−8 week young and 24 month old mice before and after experimental infection with Pseudomonas aeruginosa topically applied to the scarified cornea [23]. The young mice recovered from their infection and restored corneal clarity while the aged mice had extensive ocular destruction and corneal scarring. Conjunctival limbal DC numbers in young mice were found to be significantly increased at day seven post infection and then returned to the baseline levels. In contrast, conjunctival limbal DC numbers in aged mice were found to increase slowly and to peak at fourteen days after infection. Other differences between the two ages included an initial increase in DC five hours post infection in the young groups and an initial decrease at five hours in the aged groups of mice [23]. Using epithelial sheets from the cheek and palate mucosa, and from ear and footpad skin of three-month-old and 24-month-old mice stained for MHC class II surface antigen to demonstrate LC, Rittman et al. reported that the general distribution of such cells was unchanged with age, but those in epithelia from the old mice were more varied in shape, with irregular cell bodies and more elongated dendritic processes [24]. The numerical density of LC in old mice was reduced by up to 60 % compared with that in young mice. The densities of feline epidermal DC expressing CD18, MHC class II and CD1a antigens were determined for four anatomical locations in 19 cats. The densities of CD1a+ LC in the skin were significantly different, with young and old animals displaying less stained cells than adults [25].

Cumulatively, these results suggest that the number of DC in the epithelial tissues of aged animals are significantly decreased [26] (Table 1). This may contribute in part to the increased incidence of cancer and infectious diseases in older animals. We have recently reported that the number of DC in the spleens as well as DC generation from bone marrow hematopoietic precursors gradually decreases in aged transgenic adenocarcinoma of mouse prostate (TRAMP) mice [27]. These transgenic animals are characterized by an age-dependent development of spontaneous adenocarcinoma of the prostate. There are few reports of changes in DC in different tissues during aging. One study demonstrated altered morphology of DC in the thymus of old mice. Their cytoplasm appeared clarified, swollen, and empty as if having lost most of the cellular components [28].

Additional results were recently reported by Ishikawa et al, and provided evidence that age-dependent increased number of DC in various tissues may induce development of autoimmune diseases. They showed that CD11b+CD11c+ DC were increased in the thymus and spleen in aged (NZB×NZW)F1 (BWF1) mice developing lupus nephritis, but not in NZB and NZW mice of comparable age. These DC were also identified as the major cell source for B lymphocyte chemokine (BLC/CXCL13). Interestingly, BLC showed preferential chemotactic activity for B1 cells derived from several mouse strains, including non-autoimmune mice. Cell surface CXCR5 expression on B1 cells was significantly higher than that on B2 cells and B1/B2 ratio in the thymus was significantly higher than those in the spleen and peripheral blood in aged BWF1 mice [29]. Thus, aberrant high expression of BLC by DC in the target organs in aged BWF1 mice, serving as a model of systemic lupus erythematosus (SLE), may play a pivotal role in breaking immune tolerance in the thymus and in recruiting autoantibody-producing B cells in the development of murine lupus. The same authors have recently reported that CD11b+CD11c+ DC were markedly increased in the peripheral blood in aged BWF1, but not in similarly aged NZB or NZW mice [30]. Part of these DC showed a typical dendritic morphology and expressed MHC class II molecules, and had a weak stimulatory ability in mixed lymphocyte reaction. Since TNF-α induces BCL expression by blood and bone marrow DC in BWF1 mice and TNF-α expression is increased in aged animals, DC recruitment in the circulation and maturation into BLC-producing DC by TNF-α may play a pivotal role in the development of systemic autoimmune diseases. Interestingly, in young BBW rats developing thyroid autoimmunity, during the initial phases of the thyroid autoimmune response (before the appearance of Tg-antibodies in the circulation) numbers of thyroid DC increase, whereas in normal thyroid tissue of both human and rat DC were relatively scarce. During the later stages of the thyroid autoimmune response in old BBW rat (after the appearance of Tg-antibodies in the circulation) DC were not only present in high number, but 20−30% were seen in contact with intrathyroidal T-helper lymphocytes [31]. Accessory cell deficiency in aging has also been suggested as a cause of decreased immune response to pneumococcal vaccine [32]. Thus, decreased numbers of DC in the skin and/or their redistribution in different lymphoid and non-lymphoid tissues in aged animals might be directly associated with the progression of malignant, infectious or autoimmune diseases.

Therefore, alterations of DC numbers in the skin and other organs may be associated with impaired generation of DC in the bone marrow or accelerated immigration of these cells from the organ's compartments. It is conceivable that alterations in dendropoiesis play a primary role in DC abnormalities in aged mice. In fact, it has been recently reported that multiple imbalances in the regulatory factors derived from non-hemopoietic cells in the bones may lead to an inappropriate response of myelopoiesis in aged senescence-accelerated (SAM) mice after stimulation with LPS [33], which may play a key role in infections and tumorogenesis. Correspondingly, it was reported that aged humans and aged experimental animals exhibit a diminished ability to upregulate hemopoiesis [34-36]. Furthermore, the results of transplantation of bone marrow cells from young and old donors into irradiated recipients indicate that the decreased LC density found in old mice may result from a deficiency in LC bone marrow progenitors [19]. Our recent data directly demonstrated that induction of dendropoiesis by a well-characterized DC growth factor FLT3 ligand [37, 38] resulted in the generation of different DC subpopulations and their differential distribution in the lymphoid tissues in young and old mice [39]. Cumulatively, these data suggest that not only distribution but also DC function may be altered in aged animals.

2.2. Dendritic cell function in aging experimental animals

The most important function and hallmark of DC is their ability to activate T cells and induce their proliferation. This function of DC is commonly tested in vitro in mixed cell cultures with reliable and reproducible results [40]. Haruna et al. have examined the age-related changes in the function of DC using a substrain of senescence-accelerated mouse (SAMP1) [41]. In the primary mixed leukocyte reaction (MLR), DC from aged SAMP1 mice showed less stimulatory activity than those of age-matched BALB/c or young SAMP1 mice. Interestingly, these age-related decreases in the stimulatory activity of antigen-presenting cells were found to be related to the changes in the surface density of MHC class II and intercellular adhesion molecule-1 (ICAM-1) but not B7−1 (CD80) or B7−2 (CD86) costimulatory molecules on DC. Sprecher et al. studying epidermal DC concluded that the in vitro ability of LC from aged mice to stimulate the proliferation of sensitized T cells in the presence of the sensitizing antigen was impaired when compared with young mice [19]. However, the capacity of LC to transport antigen in vivo from the skin to the draining lymph nodes was found to be comparable to that of young mice. Interestingly, Komatsubara et al. found that in mice the stimulatory capacity of DC cells in the both allogeneic and syngeneic MLR might both increase or decrease with age, depending on the mouse strain and was not associated with the expression of MHC molecules [42, 43].

Using allergic contact sensitivity response to trinitrochlorobenzene (TNCB) as a functional test for murine LC, Choi and Sauder reported that although the aged animals demonstrated increased variability in their responsiveness, there was no overall difference in this example of cutaneous immunoreactivity between aged and young animals [21]. In contrast, using the same model, Gu et al. concluded that contact allergy may be diminished in aged mice: the ear swelling indices, as an indicator of the contact sensitivity, of 8−10-week old group were significantly higher than those of 40−48-week old group from 18 h to 5 days [44, 45]. A significant decrease of the densities of MHC class II+ dermal DC from 18 h to 48 h, followed by a gradual increase reaching significant increase of the densities of dermal DC from 5 days to 21 days in both 8−10 week and 40−48 week groups, was also observed, although in the normal control groups a significant decline of MHC II+ DC in the 40−48-week old group was noticed [45].

Recently it has been reported that LC mobilization and the subsequent accumulation of DC in regional lymph nodes in response to topical challenge with a chemical allergen is less vigorous in older mice [22]. Flow cytometric analysis of DC derived from the draining lymph nodes of fluorescein isothiocyanate (FITC)-sensitized mice revealed that the frequency of FITC+ DC arriving in draining lymph nodes was also reduced in older mice although the fluorescence intensity was comparable. Control and allergen-treated older mice also displayed decreased total lymph node cellularity [22]. Furthermore, contact hypersensitivity responses were found not to be compromised in older mice. However, the cytokine regulation of LC migration in the two age groups of mice was quite different: migration of LC induced by intradermal injection of TNF-α was markedly reduced in older animals, whereas the percentage of LC that migrated in response to IL-1β was comparable for both young and aged mice [22]. Since both allergen- and TNF-α-induced LC responses are known to require an IL-1β signal for effective migration, the authors suggested that impaired LC migration in older mice might be due to a reduced availability of epidermal IL-1β. Furthermore, in the different aging animal model, DC from lymph nodes show degenerative characteristics with decreased adhesion molecule expression, less dendrite formation, and reduced antigen trapping capacity, which together imply disruption of functional activity [46].

Analyzing activation of T cells by APC, Plowgen et al. demonstrated that with age, the duration of APC-T cell contact time required to achieve clonal expansion increased [47]. Although naive CD8+ T cells from aged mice showed no defect in antigen-induced proliferation when stimulated with APC from young mice, they exhibited reduced clonal expansion and secreted significantly lower amounts of IFN-γ when stimulated by APC from aged mice. In addition, the aged APC were defective in costimulatory molecule expression and cytokine and chemokine secretion [47]. Similarly, Donnini et al. reported that APC from old mice induced similar lymphocyte proliferative responses but lower lymphocyte cytotoxicity and a reduced number of CD8+ T cells producing IFN-γ in comparison with APC from young animals [48]. The low expression of the mRNA for the migratory CCR7 chemokine receptor present in immature APC from old mice was greatly increased in mature APC up to the levels found in APC from young animals. Interestingly, the in vivo migration of APC was higher in old than in young mice, suggesting that an increased migratory capacity of old APC may be required to balance their reduced antigen presentation to cytotoxic lymphocytes. Recently, using purified CD11c⁺CD4⁻ CD8α⁻ DC, Grolleau-Julius et al. showed that DC from old mice were 4 times less effective than young DC in stimulating syngeneic CD4⁺ T cell expansion. Old DC also produced lower levels of IL-6 and TNF-α, higher levels of IL-10 and express decreased levels of DC-SIGN [49].

Age-associated dysregulation of the immune system of the gastrointestinal tract has been well documented. Acknowledging the role played by DC in mucosal immunity, Kato et al. evaluated DC in mucosal immune compartments and their responses to either tolerogens or immunogens in the animal models [50]. The results suggest that impaired antigen-specific IgA antibody responses and lack of oral tolerance induction seen in aged mice may be associated with decreased DC functions in Peyer's patches in addition to impaired T cell responses.

Thus, despite a few contradictory reports, most experimental animal studies suggest that DC numbers, DC migratory potential, and the ability of DC to present antigens to T cells is significantly altered in aging (Table 1). This suggests the importance of experimental approaches aimed restoring impaired DC function in aged animals. Recently a report demonstrated that immunization of aged mice with Diphtheria toxoid in formulations containing unmethylated immunostimulatory CpG motifs promotes the successful development of immune responses that are qualitatively and quantitatively comparable to those induced in young animals vaccinated in a similar manner [51]. Aged mice given vaccines containing CpG oligodeoxynucleotides (ODN, TLR ligand) expressed primary and secondary systemic humoral immune responses having isotype profiles consistent with an enhancement in Th1 type immunity. The ability to generate common mucosal immunity was also restored in aged animals given CpG ODN-containing vaccines. Importantly, DC were determined to represent one of the cellular targets of CpG ODN activities in aged mice since restoration of immune function was observed when DC from aged donors were pulsed with antigen and CpG ODN prior to injection into syngeneic young adult or aged recipients. In contrast, antigen-pulsed DC from young donors were fully capable of stimulating immune responses following their injection into syngeneic young adult or aged hosts, without need for exposure to CpG ODN [51]. Although the mechanism by which CpG DNA exerts its beneficial adjuvant effects on the aged immune system remains unclear, these exciting findings suggest that the incorporation of CpG ODN into vaccine formulations provided to the aged could prove useful in the development of more effective vaccines for the elderly.

In summary, experimental animal studies of the DC system in aging not only clearly demonstrate the overall dysbalanced distribution of DC in lymphoid and non-lymphoid tissues in aged animals, but also provide preclinical models allowing evaluation of novel experimental approaches aimed at protecting or restoring suppressed DC in aging. These studies will be extremely helpful for developing specific and effective immunotherapies for cancer.

3. Dendritic cell system in aging humans

3.1. Number of dendritic cells in the elderly

The effect of aging on epidermal LC and their response to a single ultraviolet (UV) exposure has been evaluated in skin biopsy specimens of healthy adults by many researchers. It has been demonstrated in early studies that the number of DC within human conjunctival epithelium and skin decreases in the elderly compared with young subjects and decreased numbers of LC in the sun-damaged skin of elderly individuals may play a permissive role in the development of skin cancers [52, 53].

Later studies have confirmed a decreased LC density with age in humans, but it is difficult to control for the effect of ultraviolet light in human studies. Studying biopsies from the preauricular area in 15 subjects, Ghersetich et al. revealed that DC were significantly decreased in the 57- to 75-year-old group compared to the 8- to 21-year-old group [54]. Interestingly, the application of IFN-α cream induced an increase in cutaneous CD1a+ cells and HLA-DR+ cells in older subjects. Nevertheless, linear decrease of CD1a+ DC, including LC, with aging might be considered the most important cause of reduced immunosurveillance in the skin of the elderly [54]. In similar studies, Bhushan et al. revealed that baseline values for LC frequency within epidermal sheets were significantly different between young (1156.3 ± 38.5 cells mm²) and elderly subjects (835.7 ± 48.2 cells mm²) [55]. Intradermal injections of TNF-α caused a significant reduction in the frequency of LC in both elderly and young subjects. However, the extent of TNF-α-induced LC migration was substantially different between the two groups, with a mean 9% reduction in LC frequency in elderly volunteers compared with a mean 23% decrease in young subjects [55]. Given that LC migration in response to exogenous IL-1β is not compromised in aged skin [56], one can hypothesize that impaired LC migration observed in response to TNF-α in elderly subjects is not attributable to decreased responsiveness to TNF-α per se, but due to inadequate IL-1β signaling. Together, these studies suggest that there are significant differences between young and old skin with respect to both resting LC numbers and their response to different cytokines.

Thus, the hallmark of changes in LC in natural as well as UV-induced skin aging is the reduction in cell numbers within the epidermis. In addition, LC show an atrophic morphology with few dendrites, and few Birbeck granules [46]. It is assumed that these morphological changes are associated with loss of DC functions, and that this contributes to age-associated development of skin cancer [57]. It was also suggested that therapeutic strategies against natural and UV-induced skin ageing should include a reduction of these changes of LC in order to strengthen the immunological functions of the body's outer surface [46].

Indrasingh et al. studied fifty-one human palatine tonsils ranging between 4−54 years of age for quantitative analysis of LC in the epithelium using CD1a+ staining, which is a specific immunological marker for LC in vivo [58]. In the different age groups, the mean number of LC per zone of 1.1 mm length varied between 40±2 and 14±1. Interestingly, in females, there was a negative correlation between age subgroups and mean numbers, but in males there was no correlation. Overall, in all the 51 biopsies together, there was a negative correlation and significant sex and age differences [58]. Recent analysis of CD1a+ DC in the oral epithelium revealed that in the older age group (61−74years) cell density was significantly lower than in the younger age groups and morphologically, LC showed fewer dendritic-branching processes and had a rounded shape in the older age groups [59].

There are very few reports evaluating DC numbers in other tissues in aged individuals. Morphometric analysis of DC in aged human thymus revealed an age-related reduction in the number of medullary DC [60]. Varas et al. confirmed these results and showed that although the number of thymic DC declined with aging (due to the reduction of thymic cellularity), the proportion of human thymic DC remains constant between young and old individuals [61]. Recently, two subsets of DC have been identified in human blood: DC1 or earlier called ‘myeloid’ DC expressing CD11c and DC2 or ‘lymphoid’ DC expressing CD123 and now termed plasmacytoid DC. Characterizing DC1 and DC2 subpopulations of DC in human peripheral blood, Teig et al. revealed that while the number CD11c+ (myeloid) DC1 (or conventional mDC) did not change with age (mean 11 cells/μl), the proportion of CD123+ DC2 (or plasmocytoid pDC) decreased significantly from about 20 cells/μl to 8 cells/μl with age [62]. Similar conclusions were reported by Shodell and Siegal, who found significant decreases in circulating pDC in healthy aged humans, as was defined both by flow cytometry and IFN-α production: from 7.8 cells/μl for the youngest age group to 4.2 cells/μl for the oldest [63]. Using similar methodology, Della Bella et al. have recently reported that the number of myeloid DC in peripheral circulation progressively declines with age [64]. This finding was accompanied by a decrease of CD34+ precursors and increase of circulating monocytes, suggesting that the entire differentiation process of antigen presenting cells is partially dysregulated in the elderly. As the two subpopulations of DC preferentially recognize different pathogens and produce different cytokines, age-related changes may play a role in the development of the immune responses.

Collectively, these studies demonstrate that, similar to the results obtained from animal studies, the numbers of DC, their distribution, and potentially their generation and development from hematopoietic precursors (dendropoiesis) in vivo are markedly inhibited in the elderly (Table 2).

Table 2.

Alterations of the DC system in aging humans

DC function	Model	Note	Year	Ref
An early demonstration of an age-associated loss of epidermal LC	LC were assessed by histochemistry	Following irradiation of the skin, LC disappeared in both young and old individuals, but LC number fell less rapidly in old adults	1982	[52]
The number of LC was significantly decreased in the older age group.	Histochemical and morphological detection of LC	Decreased numbers of LC in the sun-damaged skin of elderly individuals may play a critical permissive role in the development of cutaneous carcinoma	1984	[53]
APC from aged individuals were equally effective as those from young persons in their ability to restore mitogen-induced proliferative activity of aged T cells	T lymphocyte proliferative responses to various mitogenic stimuli in accessory cell-dependent and - independent systems	The authors suggested that the age-associated diminution in T cell responsiveness was due, at least in part, to specific deficiencies in T cell/APC communication	1990	[69]
The number of medullary DC in the thymus was reduced with age	IHC and morphometric analyses		1990	[60]
LC were reduced in aged skin	HLA-DR+ cells		1991	[100]
APC from healthy aged might be deficient in providing appropriate T cell stimulation	Mitogen-induced proliferation of T cells with and without APC		1992	[68]
Linear decrease of CD1a+ cells with aging	Analysis of CD1a and HLA-DR cells in biopsies from the preauricular area by IHC	Application of IFNα cream induced an increase in cutaneous CD1a+ cells and HLA-DR+ cells in older subjects	1994	[54]
The LC density per mm2 of tongue epithelium in the older age groups was significantly lower than that in the younger age groups	Histomorphometrical analysis		1994	[101]
No significant effect of age on mucosal or skin LC density was found	CD1a+ cells in biopsies of buccal mucosa, lip, hard palate, lateral border of tongue, floor of mouth and abdominal skin		1994	[102]
A basic decline in the density of LC corresponding to advancing age of the tissue donors was found in all regions of conjunctival epithelium studied	LC were assessed as CD1a+ cells		1995	[103]
DC from young and old individuals expressed similar pattern of surface molecules and were equally effective in inducing the proliferation of tetanus toxoid-specific T cell clones	PBMC-derived DC generated with GM-CSF and IL-4	Larger numbers of DC were obtained from old individuals than from young ones	1996	[65, 66]
Unstimulated DC from young and old individuals had a similar surface expression of MHC class II and CD54 and secreted moderate amounts of IL-12 and TNF-α	Phenotype and cytokine production in blood-derived DC	Stimulation of DC with influenza vaccine led to a marked and equal increase in the expression of surface molecules and cytokines in cells from young and old individuals	1998	[70]
Age-associated alterations in LC numbers	Quantitative analysis of LC by IHC using CD1a in the epithelium, subepithelial tissue, follicles and interfollicular areas	Significant sex differences were also observed	1999	[58]
No differences in maturation, cytokine production, stimulating the proliferation and the cytokine production of T cells between DC from young and old persons were observed	Monocyte-derived DC	The generation of DC from blood monocytes in response to GM-CSF and IL-4 treatment was similar in cells from young and old persons	2000	[67]
The expression of HLA-DR in DC of the elderly subjects was significantly decreased when compared to the young controls	Three-color flow cytometry of peripheral blood DC	The expression of various other surface markers on DC was similar in the young and elderly subjects. The ability of transendothelial migration of DC was found to be unimpaired in the elderly subjects.	2000	[71]
LC show an atrophic morphology with few dendrites, and few Birbeck granules in aged subjects			2001	[46]
Numbers of pDC in peripheral blood and the production of IFN-α declined significantly with aging	Flow cytometry analysis of blood DC and IFN-α production	CD4+ T cells decreased by approximately 20% over the same age range, while there was no change in the total lymphocyte or monocyte counts.	2002	[63]
While the number of mDC did not change with age, the proportion of pDC decreased significantly	FACScan analysis of peripheral blood DC subpopulations		2002	[62]
LC frequency was significantly higher in young than in elderly subjects	Immunofluorescent staining for the CD1a+ LC marker in epidermal sheets	Intradermal injections of TNF-α caused a mean 9% reduction in LC frequency in elderly volunteers compared with a mean 23% decrease in young subjects	2002	[55]
The number of DC in the thymus decreased with age The levels of expression of MHC II, CD80, CD86, CD54 and mainly CD40 were reduced in the old DC population Allostimulatory capacity of old DC was decreased	Thymic DC purification and analysis (FACScan, MLR)	Although the number of thymic DC reduced with age, their proportion remained constant between young and old individuals	2003	[61]
Baseline epidermal LC frequencies were reduced at 23 % in aged subjects compared with those of young subjects	LC in punch biopsies	Exposure to IL-1ß resulted in 16% and 22% decrease in LC frequency in the skin of both young and aged donors, respectively	2004	[56]
A high autologous MLR in response to stimulation with DC in the absence of antigen was reported in both age groups	Monocyte-derived DC		2004	[104]
Lower density of DC in the oral epithelium in the older age groups	IHC analysis of CD1a DC in gingival epithelium	Morphologically, LC showed fewer dendritic-branching processes and had a rounded shape in the elderly	2006	[59]
The number of myeloid DC progressively declines with age. DC from aged individuals have a more mature phenotype and impaired ability to produce IL-12 upon stimulation	Flow cytometric analysis of whole peripheral blood samples	Peripheral blood DC from healthy subjects aged 20−92 years. The analysis was extended to circulating CD34+ cells and monocytes, that both represent DC precursors	2006	[64]

APC, antigen-presenting cells; DC, dendritic cells; IHC, immunohistochemistry; LC, Langerhans cells; MLR, mixed leukocyte reaction.

3.2. Dendritic cell function in the elderly

Comparing human monocyte-derived cultured DC in vitro, no differences in the expression patterns of surface molecules and the antigen presenting capacity between DC generated from young and old subjects were found [65]. In fact, comparable numbers of DC were generated in vitro from both young and old individuals. DC from aged persons also survived better under culture conditions. When tested for their antigen-presenting capacity, in vitro generated DC from young and old individuals were equally effective in inducing the proliferation of tetanus toxoid-specific T cell clones after antigenic stimulation [65]. Furthermore, analyzing how DC from young and old healthy individuals could affect T cell responsiveness to antigen in an in vitro senescence model, the same team concluded that DC from old individuals were as effective as cells from young donors [66]. Similarly, Lung et al. reported that the generation of DC from blood monocytes in the presence of GM-CSF and IL-4 was similar in cultures from young and old persons [67]. The DC population had a typical dendritic morphology and expressed DC surface markers, such as HLA class II, CD1a, CD11c, CD54, CD80 and CD86. DC from young and old subjects produced IL-12 and TNF-α and responded equally well to maturation-inducing stimuli. When tested for their antigen-presenting capacity, DC from young and old persons were capable of stimulating the proliferation and the cytokine production of T cells [67]. Other have also concluded that accessory cells obtained from healthy old people are equally effective as those from young persons in their ability to restore mitogen-induced proliferative activity of aged T cells [68, 69]. In another study, expression of immunoregulatory molecules and the production of cytokines was compared in blood-derived DC from old and young healthy individuals following stimulation with inactivated influenza virus [70]. Non-stimulated DC from young and old individuals had a similar surface expression of MHC class II and CD54 and secreted moderate amounts of IL-12 and TNF-α. Stimulation with influenza vaccine led to a marked increase in the production of surface molecules and cytokines with changes equally pronounced in cells from young and old individuals.

In contrast, it was also reported that the in vivo expression of HLA-DR in the peripheral blood DC of elderly subjects was significantly decreased when compared to young control subjects [71]. However, expression of various other surface markers was similar in the young and elderly individuals. Furthermore, the ability of transendothelial migration of DC was found to be unimpaired in the elderly subjects. In the migrating DC of the elderly volunteers, a significantly increased expression of CD11c was observed, whereas the expression of CD54 was significantly enhanced in the migrating DC of the young subjects [71]. However, others concluded that it was possible that DC may have an impaired potential to cross tissue barriers and trigger immune response in vivo [72]. Interestingly, comparing peripheral blood DC from healthy subjects 20−92-year old, Della Bella et al. reported that DC from aged individuals appeared to have a more mature phenotype and impaired ability to produce IL-12 upon stimulation [64].Analyzing thymic DC from old and young subjects, Varas et al. reported that although almost all thymic DC express MHC class II, CD86, CD40, and CD54, the level of expression of MHC II, CD80, CD86, CD40, and CD54 was markedly decreased on those DC from old individuals [61]. Furthermore, isolated old thymic DC were less efficient in inducing proliferation of allogeneic T cells than thymic DC isolated from young individuals.

Together, these findings indicate that in old individuals in vivo DC of the systemic immune system are reduced in their functional capacity to stimulate immune responses, whereas DC generated ex vivo from precursor cells are fully functional, and therefore might be used in therapeutic approaches to treat age-associated malfunctions of the immune system [46]. Thus, it is likely that DC precursors have a preserved capacity to differentiate into functionally active DC in the elderly; however, they require appropriate stimulation. In fact, evaluating in vitro hemopoiesis and hemopoietic cytokine production in 9 centenarians (median age 100.5 years, age range: 100−104 years), 10 old people (median age: 71 years, age range: 66−73 years), and 10 young people (median age: 35 years, age range: 30−45 years), Bagnara et al. demonstrated a well-preserved capability of CD34+ cells from old people and centenarians to respond to hemopoietic cytokines, and to form erythroid (BFU-E), granulocyte-macrophagic (CFU-GM), and mixed colonies (CFU-GEMM) in a way (number, size, and morphology) indistinguishable from that of young subjects [73]. This finding provides an explanation for the above-mentioned studies demonstrating that DC responsiveness to stimulation with a viral vaccine is unimpaired in old age and DC from old persons may still function as powerful antigen-presenting cells (APC) if provided with the right differentiation and maturation stimuli (Table 2). It is possible that DC1 derived from elderly subjects have intact functions and a normal phenotype. However, there are no studies, which have fully evaluated DC2 populations in the elderly, although these DC might play a crucial role in the development of immunosuppression in aging.

It is also important to realize that unlike the healthy elderly who demonstrate impaired T cell function but intact APC function [74, 75], the frail elderly may display multiple defects in both T lymphocytes and APC function [11]. The authors hypothesized that age-related T cell deficits might be associated with compensatory boost in antigen-presenting functions in the healthy elderly. They stated that preliminary findings of their ongoing studies point to reduced antigen presentation, costimulatory molecules and IL-12 production in the DC population of the frail elderly. Interestingly, the production of an immunosuppressive cytokine IL-10 by APC is elevated in elderly individuals and may play a role in the age-related dysbalance of immune function [75]. In the study of Looney et al., autologous DC were used as antigen-presenting cells to induce in vitro cytokine production in response to respiratory syncytial virus (RSV) and influenza infections in 11 “young” (mean age 31 years) and “older” (mean age 75 years) healthy volunteers [76]. They found that older subjects produced significantly less IFN-γ in response to RSV than the younger subjects. This defect in cellular immunity may be related to the increased morbidity observed with RSV infection in elderly persons. Since the frail elderly respond poorly to immunization and may represent up to 70% of elderly subjects (>65 years), impaired function of antigen presenting cells may be a serious problem that only becomes apparent under situations of immunologic stress.

In conclusion, DC may represent a potent tool for immunotherapy and are likely to increase the efficacy of vaccines in the elderly. Additional studies and clinical trials are necessary to determine whether in vitro generated DC can induce specific antitumor immune responses in old patients and what can be done to restore or improve impaired DC in vivo in aged patients with cancer. These studies are needed for the rational development of the next generation of anticancer vaccines with improved efficacy for old cancer patients.

4. Age-induced and tumor-induced immunomodulation of the dendritic cell system in patients with cancer

Immune system alterations during ageing are complex and pleiotropic, suggestive of remodeling or altered regulation, rather than a simple immune deficiency. Currently 60% of all neoplasms occur in persons aged 65 years and older, and this percentage is expected to increase as the population ages [77]. For instance, 80% of diagnosed prostate cancer, the most common malignancy in American men, occurs in patients 60 years and older. Tumor development and aging can each alter immune competence. Unfortunately, few studies explain how the presence of tumor further compromises the immune dysfunction that accompanies aging. Young et al. have evaluated the impact of lung carcinoma on immune parameters of middle-aged (averaging 6.5 months) versus aged (averaging 21.3 months) mice [78]. The results revealed that spleen and lymph node cultures from aged tumor-bearing mice had the lowest frequency of CD4+IFN-γ+ cells and the least amount of secreted IFN-γ. Interestingly, the authors have also demonstrated that aging impacts the mechanisms by which tumors typically inhibit T cell function [78].

There is increasing evidence that impaired hemopoiesis and deregulated cytokine, chemokine and growth factor networks have important implications for cancer in the elderly. In aged people, hemopoiesis is dysregulated and becomes paradoxically down-modulated under situations of increased hemopoietic demand [79]. Even though basal hematopoiesis is maintained in aging, the ability to respond to hematological stress is blunted, and the capacity for stem cell self-renewal also appears to decline gradually [80]. Furthermore, there are also indications that the frequency of CD34+ hematopoietic precursor cells progressively declines with age, suggesting that in aged subjects this deficiency may contribute to the reduced frequency of DC. [Della Bella, 2006 #727]. In fact the authors' finding of a significant decrease of myeloid DC, or DC1, along with ageing may be relevant to the reduced capacity of aged people to generate efficient anti-infectious and antitumor immune responses.

The balance between different subpopulations of T cells, their proliferation and the Th1/Th2/Treg cytokine network plays a crucial role in immune homeostasis and is involved in the regulation of many immune-mediated and inflammatory diseases and abnormalities including cancer [81, 82]. An age-associated decrease in the expression of IL-2 may contribute to impaired cellular immunity. Results from several laboratories have demonstrated that the ability to produce IL-2 declines with age. Additionally, the increased IL-6 production frequently found in the elderly may contribute to the increased incidence of multiple myeloma with age. Dysregulation of the expression of these and other cytokines may be a mechanism contributing to age-related impairment of the hemopoietic response; the genesis of specific malignancies; and cancer cachexia. For instance, Candore et al. have reported the results of a study performed to determine the influence of age on the capacity to produce IFN-γ, IL-4, and IL-6. Mononuclear cells from young and old subjects were assessed for cytokine producing capacity in response to PHA stimulation. A significant decrease of IFN-γ production by old subjects has been observed. However, no significant difference was observed between the old subjects and the young ones as regards IL-4 and IL-6 production in this study. The authors suggested that this imbalanced cytokine production may well account for the pattern of immune response which may be observed in elderly, i.e. a normal or increased humoral response in face of an impaired T cell immune response [83].

Furthermore, primary or secondary increased levels of IL-6 and IL-10 repeatedly reported in old individuals might have a direct effect on dendropoiesis and/or maturation of DC. We and other have recently reported that these cytokines, as well as TGF-β, VEGF, M-CSF and others, may markedly inhibit the generation, maturation and function of DC both in vitro and in vivo [14, 84-86]. The DC system appears to be significantly impaired in the tumor microenvironment and usually manifests as decreased dendropoiesis and DC maturation, suppressed ability of DC to produce IL-12, increased synthesis of IL-10, inability to induce T cell proliferation and shortened survival of DC [14]. Furthermore, abnormal balance between cytokines, chemokines and growth factors in the tumor environment has a direct impact on the activity and longevity of different DC subpopulations locally and systemically [87]. It is conceivable that aging might additionally down-regulate the DC system in cancer and worsen tumor-induced immunosuppression and immune imbalance, which in turn may further augment different tumor immune-escape mechanisms. For instance, one can speculate that DC2 cells in aged cancer patients may produce increased levels of IFN-α, shift Th1/Th2 balance to type 2 cytokines and may induce T cell tolerance to different antigens. In fact, it has been shown that NK cells from aged mice are more sensitive to IFN-α-induced apoptosis than NK cells from younger animals [88] and a dysregulation in the Th1/Th2-system, which is predominated by Th2-functions, has been demonstrated in the elderly [89, 90]. Similarly, increased production of IL-10 by tumor-treated aged DC1 may further shift cytokine balance to Th2, suppress antitumor immunity and increase the risk of tumor-specific tolerogenic responses. Interestingly, it has been recently shown that vaccination of young and old mice with a HER-2/neu DNA plasmid, which is mediated by DC, resulted in complete protection of young mice from subsequent HER-2-expressing tumor challenge, whereas less than 60% protection was observed in old mice [91].

Although many studies have demonstrated the efficacy of autologous DC vaccines in stimulating the antitumor immune response in the young, none of them have considered the potential impact that aging may have on the immune system or test whether DC-vaccination is effective in old hosts. Using ovalbumin (OVA)-expressing tumor cells, Shi et al. demonstrated that in comparison to young mice, aged mice were 10-fold more susceptible to tumor cell challenge [92]. Aged mice immunized with bone marrow-derived DC pulsed with OVA survived for significantly shorter periods after challenge with OVA+ tumor cells as compared to equivalentally treated young mice. Furthermore, CTL from aged mice immunized with OVA-pulsed DC displayed 4-fold weaker cytotoxicity as compared to CTL from immunized young mice. Similar data were reported by Grolleau-Julius et al, who examined the effect of aging on the generation and on the three major functions (CD4⁺ T cell stimulation, cytokine production, and tumor surveillance) of carefully characterized bone marrow-derived murine DC [49]. These results clearly demonstrate that mice bearing ovalbumin-expressing melanoma and treated with the ovalbumin peptide-pulsed young DC exhibited significantly greater tumor regression than mice treated with ovalbumin peptide-pulsed old DC. Recently, Sharma et al. also compared the efficacy of DC vaccines in young and old mice [93]. They revealed that DC-vaccination in young animals induced an antitumor response resulting in 60% tumor growth inhibition, while only minimal protection was observed in old animals. Importantly, co-administration of anti-OX-40 or anti-4−1BB with tumor-cell-pulsed DC vigorously enhanced the antitumor immune response in both young (85−90% tumor growth inhibition) and old (70−75% tumor growth inhibition) mice. Together with our data demonstrating the strong antitumor potential of DC transfected with the CD40L, RANKL or 4−1BBL genes [94], these data suggest that special attention should be given to members of the TNF superfamily in terms of improving antitumor DC vaccines in older patients.

Although, several studies have shown that immunotherapy can be effective in young, but not old animals, it remains unclear if the antitumor efficacy of immunotherapeutic protocols (or lack thereof) is a function of age. Thus additional studies of the DC system in aged cancer patients are needed to delineate the potential synergistic immunosuppressive effect of aging and cancer, and to devise strategies to circumvent these deficits, in order to improve the immune responses of older cancer patients.

5. Concluding Remarks

DC play a key role in maintaining host integrity through their involvement in host defense and immunity. Although we are now beginning to understand DC and how important they may be in the modulation of immune responses, much remains to be learned about these cells. DC have received increasing attention due to their potential value as biological adjuvants in tumor vaccines and their involvement in the immunobiology of tolerance and autoimmunity. Although age related changes of immune functions have been extensively investigated by gerontologists, the literature on potential alterations of DC with aging is scarce. Clearly, more studies are needed to elucidate the role in aging of different subpopulations and subsets of DC. Using DC, it might become possible to increase immunoreactivity, prolong immunological memory and maintain an intact T cell repertoire in old age. Finally, the success rate of cancer vaccines, including DC-based vaccines, may depend on the strategies selected for their delivery. The development of preventive cancer vaccines for the elderly is an important future goal in view of the increased susceptibility to malignancies with aging.. Since drug treatment is more toxic for the elderly than for young adults [95], a combination of a short drug therapy (with less severe side effects) to destroy the tumors, followed by vaccine-based therapy to eliminate the remaining or residual and/or metastatic tumor cells, would be especially important for elderly cancer patients. Clearly, more studies on DC in both frail and healthy elderly are necessary to understand the impact of aging on the immune responses.

Figure 1. Alterations of the dendritic cells system associated with aging in animals and humans.

DC, dendritic cells; mDC, myeloid DC (or DC1); pDC, plasmacytoid DC (or DC2); LC, Langerhans cells; LN, lymph node; co-stim, costimulatory molecules; Adh, adhesion molecules; spl, spleen; b/m, bone marrow; ↑, up-regulation; ↓, down-regulation; 0, no effect; ?, remained to be determined.

Short biographies of the authors

Michael R. Shurin, MD, PhD, D (ABMLI) is an Associate Professor of Pathology and Immunology and Associate Director of the Division of Clinical Immunopathology at the University of Pittsburgh Medical Center, Pittsburgh, PA, USA. He received his medical education and his PhD degree in Moscow, Russia and from 1991 he was a faculty at the University of Pittsburgh. Dr. Shurin's research laboratory focuses on the mechanisms of abnormal functioning of the dendritic cell system in the tumor environment and on designing and testing novel dendritic cell vaccines in cancer. He is an author of more than 100 publications.

Galina V. Shurin, PhD is an Assistant Professor at the Department of Pathology, University of Pittsburgh Medical Center. Her research interests include molecular mechanisms of tumor-mediated dysbalance of dendritic cell differentiation and function, molecular analysis of intratumoral microenvironment in vivo, age-related alterations of the dendritic cell system and the effects of cytokines, chemokines and growth factors on dendritic cell function and longevity in tumor-bearing hosts. She is known for her pioneering studies identifying tumor-derived factors responsible for suppression of dendritic cell generation and activity, as well as for her research demonstrating a unique role of IL-15 in immunobiology of dendritic cells.

Gurkamal S. Chatta, MD is an Associate Professor of Medicine at the University of Pittsburgh Cancer Institute (UPCI) and is the Co-Program leader of the Cancer and Aging program at UPCI. He received his medical education at Delhi University, India, and underwent fellowship training in both Gerontology and Medical Oncology at the University of Washington, Seattle, WA. His research interest is focused on developing prostate cancer vaccines in both mouse models and humans, and simultaneously delineating age-related changes in immune function in elderly cancer patients.