Immune response and inflammation in cancer health disparities

Abstract

Cancer death rates vary among population groups. Underserved populations continue to experience an excessive burden of lethal cancers that is largely explained by health care disparities. Yet the prominent role of advanced stage disease as a driver of cancer survival disparities may indicate that some cancers are more aggressive in certain population groups than others. The tumor mutational burden can show large differences among patients with similar stage disease but differences in race/ethnicity or residence. These dissimilarities may result from environmental or chronic inflammatory exposures, altering tumor biology and the immune response. We will discuss the evidence that inflammation and immune response dissimilarities among population groups contribute to cancer disparities and how they can be targeted to reduce these disparities.

Introduction

Despite a global decline in cancer death rates, patients of African descent bear a disproportionate burden of cancer lethality for some of the most common cancer types (Box 1) [1]. In the US, incidence and mortality rates for prostate, lung and colorectal cancer are higher for African Americans (AA) when compared to European Americans (EA) [2, 3]. Although age-adjusted incidence rates for breast cancer are slightly higher for EA women (140.4/100,000) compared to AA women (124.9), age-adjusted mortality rates are increased in AA women (26.8/100,000) compared to EA women (19.3) [4]. Deciphering the sources of these disparities is challenging and multi-faceted. Studies have shown that differences in access to health care and delays in treatment contribute to the overburden of prostate and breast cancer deaths in populations of African descent [5–7]. Even after adjusting for disparities in access to health care, however, these disparities remain [8], suggesting additional causes contribute to the poorer survival outcomes in these historically understudied populations.

Box 1. The burden of global cancer disparities for people of African descent.

All have not benefitted equally from the global decline in cancer death rates. Disparities in cancer incidence and mortality rates are evident for many major cancer sites. Socioeconomic inequalities, significant differences in risk factor exposures and late-stage diagnosis are all contributing factors. Cancer patients in Sub-Saharan Africa and in the central and southern parts of Asia and the Americas bear a disproportionate burden of cancer lethality for some of the most common cancer types. This is also the case for certain patient groups in the United States [1]. Cancer patients from Africa or of African descent continue to experience a higher burden of cancer incidence and mortality for many of the world’s most common cancers. For example, men in Sub-Saharan Africa and the Caribbean, and men of African descent in the United States and England, continue to have higher rates of fatal prostate cancer than other men [86]. In the United States, African Americans (AAs) also have the highest death rates from lung cancer [71]. In breast cancer, the disparity between AA and European American (EA) women in the United States persists, equating to a 40–50% increase in breast cancer death among AA women when compared to EA women [3]. Breast cancer is also a leading cause of cancer death in Sub-Saharan Africa. Expanded access to care, more diverse participation in clinical trials and enactment of policies to dismantle systemic racism are all needed to fully tackle the burden of cancer disparities on people of African descent.

The prominent role of advanced stage disease in explaining some of the survival health disparities in the United States [9] raises the question whether some patient groups may develop more aggressive disease than others because of environmental exposures, persistent chronic inflammation, comorbidities, or ancestral factors. Intrinsic differences in tumor biology and inflammatory pathway responses are well established for certain cancer types, resulting in a population-specific disease etiology [10–13]. Immune response can differ across population groups due to ancestral factors and environmental exposures [14]. Distinct germline genetic variations and alternate splicing in immune-inflammation-related genes have been detected between different population groups [15]. Study participants of African and European ancestry showed a differential immune response to infections potentially due to adaptations after exposure to infectious pathogens endemic to different regions of the world [16]. Circulating levels of some cytokines have been shown to differ between population groups because of ancestry and environmental influences [17]. These differential immune responses may have consequences and contribute to cancer disparities because of their impacts on cancer progression and therapy response.

In this review, we will present recent advances that describe immunologic differences in cancer biology between population groups but focus on the comparison between AA and EA patients, as almost all existing data has been generated from research of these two patient groups. We will discuss breast, lung, colorectal and prostate cancers as they are the top four most commonly diagnosed cancers worldwide and leading causes of cancer death [1]. We will highlight the evidence that inflammation and immune response dissimilarities contribute to cancer disparities and discuss how these distinctions can be targeted through prevention and therapy to reduce these disparities. Furthermore, we will evaluate the evidence that some of these differences may specifically influence the metastatic process.

Breast Cancer

Inflammatory signaling may excessively affect African American breast cancer patients: an opportunity for targeted prevention and therapeutic intervention

Systemic inflammation increases cancer risk. Although anti-inflammatory drugs, like aspirin, have a rather modest protective effect in preventing breast cancer in an unselected population, they may reduce the risk of estrogen receptor (ER)-negative breast cancer in AA women [18], consistent with a distinct role of inflammation in the development of aggressive disease among these women (Figure 1). There is a growing appreciation for the role of inflammatory signaling molecules in regulating the immune response to an evolving breast tumor. One important cancer risk factor, obesity, impacts AA and Latina breast cancer patients more so than EA patients, and leads to an inflammatory tumor microenvironment in breast tumors and the expansion of pro-tumorigenic crown-like structures (CLSs) that are composed of activated macrophages and dead adipocytes [19]. CLSs are more commonly found in breast tumors of AA patients and their presence tends to associate with decreased breast cancer survival [20, 21]. Recent studies have also identified significant differences in T-cell signatures across population groups, including a unique T-cell exhaustion signature that may have implications for decreased survival in AA women (Box 2).

Figure 1:

Aspirin may have a more robust benefit as a cancer prevention tool for African Americans (AA) in certain cancer types. In breast cancer, AA women who are aspirin users show a decreased risk of ER- breast cancer [18]. For lung and prostate cancer, aspirin is associated with a reduced risk of mortality in AAs [64, 75]. These findings require validation but show promise for aspirin, and perhaps other drugs targeting inflammation, as a precision medicine prevention approach to reduce the existing survival disparities for certain cancer types.

Box 2. T-cells and breast cancer disparities.

Historically, investigations of breast cancer were the first that described differences in the immune content of tumors between patient groups comparing women of African and European descent, noticing increased numbers of tumor-infiltrating macrophages in AA and African women [87, 88]. Others reported an increased density of CD8+ T-cells in breast tumors of young AA women and AA women with aggressive forms of breast cancer [89]. This supports the hypothesis that a more active and prolonged inflammatory immune response exists in individuals of African descent and promotes more aggressive breast cancer.

Various studies have provided solid evidence for marked differences in the tumor immune environment between AA and EA women with breast cancer [34, 89, 90], including an overall higher immune content score in AA patients as demonstrated by increased T-cell tumor infiltrates [34, 90]. Additional studies found indirect evidence for differences in the abundance of T-regulatory (Tregs) and T-helper type 2 cells in AA patients as compared to EA patients [90, 91]. Another study further postulated that the expression of the atypical chemokine receptor 1 (DARC/ACKR1), which is controlled by a West African ancestral genotype, rs2814778, shapes the immune environment of breast tumors [90]. Most interesting, however, is the observation of a signature of T-cell exhaustion that occurs commonly in AA breast cancer patients. The signature distinguished these patients from EA patients [34]. In this report, the authors found a higher immune cell content in AA breast tumors, but also observed that exhausted CD8+ T-cells accumulate in the same tumors. Using a derived T-cell exhaustion signature, they confirmed an association of this signature with poor survival. Thus, even though the immune cell content might be higher in AA breast tumors, the antitumor immune response in AA patients might be inhibited because of T-cell exhaustion.

Although no studies have investigated differences in response to immunotherapy based on differential CD8+ T-cell exhaustion signatures between AA and EA women, one study has shown that exhausted CD8 T-cells predict the response to anti-PD1 therapy in women with ER-positive breast cancer [92]. These provocative findings should be taken a step further and investigated in the context of differential T-cell exhaustion signatures by population group and estrogen receptor status.

Pro-inflammatory molecules contribute to mechanisms associated with breast cancer risk and progression and have been shown to differ by population group [22, 23]. A previously described five-gene classifier in the tumor stroma of AA women, consisting of PSPHL, CXCL10, CXCL11, ISG20, and GMDS [24], has the hallmark of an interferon-γ (IFNγ) signaling signature, suggesting that stromal interferon signaling is increased in these patients. IFNγ enhances tumor immunogenicity by serving as the master regulator of Th1 response and enhances patients’ response to immune therapy [25]. Tumors with an interferon-stimulated gene signature are susceptible to inhibition of adenosine deaminase acting on RNA (ADAR1) [26]. These inhibitors are currently being developed as cancer therapy agents. Thus, AA women with breast cancer and the interferon signature may show more favorable responses to both immune therapies and inhibitors of ADAR1 (Figure 2). Lastly, the finding that inflammation-inducible nitric oxide synthase (NOS2) is linked to poor survival in ER-negative breast cancer [27, 28] provided key support for a clinical trial (Phase 1b/2, NCT02834403; https://clinicaltrials.gov/ct2/show/NCT02834403) that targets refractory triple-negative breast cancer (TNBC) with a NOS inhibitor together with taxane chemotherapy. AA breast cancer patients may also respond favorably to this therapy and should be recruited into those trials.

Figure 2:

Targeting enhanced interferon (IFN) signaling in tumors and systemic inflammation to improve survival among all cancer patients - but with a potential impact in reducing survival health disparities [26, 54, 67, 75].

Immunotherapy of breast cancer may reduce the survival health disparity

Unlike other solid organ tumors, breast cancer has long been considered more immunologically “cold”, particularly the ER-positive disease, although recent advances have shown that other breast cancer subtypes, like TNBC, have higher densities of tumor infiltrating lymphocytes [29], making it a potential target for immunotherapy. Multiple studies have shown that the immune content in breast tumors associates with survival in ER-negative breast cancer, pointing to the critical importance of the immune environment in therapy response [30, 31]. Cytotoxic chemotherapy has been the main systemic treatment for women with TNBC, including use of anthracyclines and taxanes. Nonetheless, immunotherapies have recently shown promising results in improving progression-free survival for those with TNBC [32]. Immunotherapies currently in use to treat select groups of patients with TNBC include PD-1 (pembrolizumab) and PD-L1 (atezolizumab) inhibitors, which enhance the immune system’s ability to shrink the tumor using T-cell related mechanisms (discussed extensively in [33]). These therapies could significantly improve survival outcomes for women of African descent, and likely other patient groups, as an accumulation of exhausted effector CD8+ T-cells in aggressive ER-negative breast tumors has now been revealed for AA patients [34]. These tumors may respond well to PD-1/PD-L1 inhibitors. Given the increased prevalence of ER-negative breast cancer among AA women, enhanced recruitment of these patients into clinical trials evaluating immune therapies is warranted. They may lead to higher response rates among these patients when compared to other patients, improving their survival, and thereby reducing the existing survival health disparity in breast cancer.

Prostate Cancer

Inflammation and immune response are upregulated in prostate tumors of African American men

Low grade inflammation and associated immune cells can provoke prostate cancer progression through a milieu of signaling pathways involving both innate and adaptive immune systems [35]. Unlike TNBC, prostate tumors are seen as immunologically “cold” tumors that do not respond well to immunotherapy. Yet, high levels of certain immune cell types in these tumors, including CD4+ T-cells, tumor-associated macrophages, myeloid-derived suppressor cells, and natural killer cells (NK) cells were found to be associated with worse prognosis [36–39]. An elevated immune content score in prostate tumors is associated with inferior survival outcomes, whereas an upregulated PD-L2 expression predicted worse distant metastasis-free survival and was associated with inferior radiotherapy outcomes, suggesting it may be a therapeutic target of interest either alone or in combination with radiotherapy [36]. Elevated release of cytokines IL-6 and IL-8 is also associated with adverse prostate cancer outcomes, as shown in additional studies [40, 41].

AA tumors display a distinct immunological profile when compared to EA tumors with overall higher immune cell content, enrichment of immune oncological pathways and epithelial to mesenchymal transition, and a lower DNA damage repair capacity [42–44]. In vitro studies show stromal cells from AA men with prostate cancer have enhanced expression of inflammatory mediators including TrKB, BDNF, VEGF, and IL-6 and higher immune content in the tumor microenvironment [45]. These rather robust population differences in the immune environment may provide a new understanding of the tumor biology that can be used to guide decisions on therapy. This gained knowledge may spur novel therapeutic approaches that can further improve prostate cancer outcomes in these men [46]. For example, men of African descent with metastatic castration-resistant prostate cancer (mCRPC) showed higher survival rates when treated with the cancer vaccine, Sipuleucel-T [47]. Baseline and post-treatment samples from men who received Sipuleucel-T showed increased systemic inflammation in AA men compared to EA men [48]. However, the data did not reveal why AA men would have this advantageous response to the vaccine so further studies are required.

An immune-inflammation gene expression signature, featuring upregulation of interferon pathway genes, occurs more often in prostate tumors of AA than EA men. This signature is a marker of decreased disease-free survival in prostate cancer and has previously been linked to acquired resistance to radiation and chemotherapy in breast cancer [49]. The precise origin of the immune-inflammation signature remains unknown, but its presence is associated with an interferon-λ4 genotype (rs368234815-ΔG) that is most common in individuals of West African ancestry and influences host viral response [50]. Upregulation of the immune-inflammation signature in AA tumors indicates a mechanism by which either inflammatory ancestral factors or a yet unknown infectious agent may contribute adversely to prostate cancer outcomes. Future studies should investigate why AA men develop this signature in their tumors as a potential opportunity for cancer prevention.

The influence of systemic inflammation on prostate cancer metastasis

mCRPC has a median survival of just three years and should therefore remain a key research focus (Box 3) [51]. When investigating inflammation as a driver of prostate cancer, much of the focus has been on the tumor and tumor microenvironment. However, recent studies highlight the importance of systemic inflammation and the immune environment in circulation as influencers of the metastatic process, with particular relevance to men of African descent. Pre-clinical studies have implicated immune cells including macrophages [52], Tregs [53], platelets [54] and neutrophils [55] as promoters of the metastatic process through protection of tumor cells in circulation, as well as promotion of tumor cell seeding and colonization.

Box 3. Prostate Cancer Metastasis.

The growth of prostate tissue is regulated by androgen hormones through activation of the androgen receptor. Androgen deprivation therapy is the standard treatment for advanced prostate cancer. Nonetheless, androgen mutations or alternative androgen production and oncogenic signaling can contribute to resistance to hormonal therapy [56]. If prostate tumors aren’t sensitive to hormone treatment or develop resistance to androgen therapy, castration resistant disease is diagnosed. Metastasis is a process where single tumor cell clones detach and disseminate from the primary tumor, travel through the blood and/or lymph vasculature, and grow into a secondary tumor at a distant site. Metastatic castration resistant prostate cancer (mCRPC) is a lethal disease with poor relative 5-year survival of 30% (http://seer.cancer.gov/statfacts/html/prost.html). The most common metastatic site for prostate cancer is bone but can also be found in the lymph nodes, liver, lung and brain. Current treatments for mCRPC are chemotherapy, radiation, immunotherapy and hormonal therapy with limited success. The use of PARP inhibitors, PD-1 inhibitors, and combination strategies of current treatments show promise in clinical trials but improved management and selection of suitable patients for these treatments is required to improve outcomes [46].

The odds are stacked against circulating tumor cells developing into a metastasis with many being lost in the blood stream or failing to initiate growth. However, when conditions are right, with a combination of growth factors and immune response from tumor and stromal cells, tumor clones can escape from the primary tumor, evade the systemic immune system, survive the bloodstream, and set up micrometastasis in a secondary location. There are many factors that promote prostate cancer metastasis, including the release of cytokines and chemokines by cells in the tumor, immune system, and tumor microenvironment. This promotes prostate cancer metastasis through facilitation of the epithelial to mesenchymal transition [52], contribution to resistance [56], angiogenesis and creation of favorable conditions to guide homing of tumor cells to secondary growth sites such as creation of a premetastatic niche, promotion of extravasation and endothelial attachment (reviewed in [93]). Platelet-derived factors in the systemic circulation may also promote metastasis in prostate cancer [64].

AA men with prostate cancer may have distinct immune and inflammatory responses to both established and proposed therapeutic strategies [46]. A strong focus on recruiting this population group for clinical studies targeting mCRPC could lead to additional discoveries of how immune response differences can be targeted with either already available or novel treatments for this lethal condition.

Levels of circulating immune cells may predict treatment response for mCRPC. It has been shown that abiraterone/enzalutamide-sensitive patients display different baseline levels of immune content in peripheral blood compared to treatment-resistant patients, including higher levels of plasma-derived pro-inflammatory mediators during treatment [56]. Patients with enzalutamide-resistant CRPC have higher expression of PD-L1/2 in peripheral blood dendritic cells, suggesting suppression of immune response in enzalutamide-resistant CRPC through induction of PD-L1/2 in circulating immune cells [57]. Two distinct CRPC bone metastasis molecular subtypes differentiated by their androgen receptor activity and cellular immune response have been described [58].

The metastatic process relating to inflammation and the immune environment outside of the tumor, may be affecting the survival and seeding of circulating cancer cells at distant sites with possible implications for disparate outcomes across population groups. Aspirin, the anti-inflammatory drug, has shown benefit in preventing aggressive prostate cancer, perhaps most robustly in men of African descent, suggesting systemic inflammation might drive adverse outcomes in this patient population (Figure 1) [59, 60]. The preventative benefits of aspirin have been attributed to inhibition of the inflammatory cyclooxygenase (COX) signaling pathway. Elevation of prostaglandin E2 and prostaglandin E2 metabolite (PGE-M), both products of the COX pathway, have been associated with many cancer types [61, 62], but an association with prostate cancer is not supported [63]. Instead, elevated urinary thromboxane B2 (TXB2), the stable metabolite of the eicosanoid thromboxane A2 (TXA2), associated with metastatic prostate cancer [64]. Elevated urinary TXB2 also associated with increased mortality but exclusively in AA men. Aspirin inhibits TXA2/TXB2 synthesis and inhibits the pro-metastatic effects of platelet-derived COX1/TXA2, in animal models of lung metastasis [65].

Platelets are now regarded as active drivers of metastatic progression. Thrombocytosis is associated with higher risk of colorectal cancer death - most strongly in AAs [66]. Precision targeting of inflammatory pathways such as COX2/PGE₂ axis inhibition can modulate the tumor microenvironment and enhance response to immunotherapy [67]. AAs already have demonstrably better response to some immunotherapies, so this combination treatment may address survival disparities [47]. Inhibition of platelets and platelet-derived factors including COX-1/TXA2, but also TGF-beta, IL-6 and VEGF, is a promising approach to target disparities in cancer outcomes for AAs [66]. Aspirin has the potential to prevent lethal prostate cancer through inhibition of pro-metastatic, platelet derived TXA2/B2 synthesis in circulation [66].

Systemic inflammation as a driver of prostate cancer progression is likely linked to an altered systemic immunity. Although unpublished, it was found that levels of immune-oncological proteins in the blood are distinctly associated with the population groups in which they are measured, suggesting a potential role in cancer disparities. Here, the immunome of Ghanaian men resembles the immunome of AA men more so than EA men, presumably due to the shared ancestral relationship. Proteins involved in chemotaxis and suppression of tumor immunity were significantly elevated in both Ghanaian and AA men compared to EA men. A suppression of tumor immunity signature consisting of several systemic immune-oncological markers, of which many are pro-inflammatory, associates with metastatic prostate cancer and this finding was most robust among the AA cases.

The exact cause of elevated inflammation in AA men is unknown. Genetic ancestry in immune response to pathogens [16], pro-inflammatory diet [68] and co-morbidities, such as diabetes [69], that are more prevalent in AA men have all been implicated. These differences in immune-inflammation pathways may be contributing to the disproportionate burden of prostate cancer lethality in AA men, but may also offer some opportunities for targeted therapies (discussed extensively in [46]), including targeting the patients with anti-inflammatory drugs, cancer immunotherapies beyond Sipuleucel T, or ADAR1 inhibitors.

Lung Cancer

Systemic inflammatory markers are associated with lung cancer

Like other cancers, reducing or eliminating disparities in lung cancer incidence and mortality is impeded because our current knowledge of lung cancer biology is derived primarily from populations of European descent. Smoking, asbestos, and infectious diseases are known to cause inflammation in the lung with established links to carcinogenesis. With different smoking patterns in AAs compared to EAs, the etiology of lung cancer appears to differ between groups. However, despite this strong rationale, in comparison to other cancer sites, fewer studies have assessed the role of systemic inflammation and the immune response in the disparate outcomes experienced by AAs with lung cancer. For the studies that have been completed, a picture is cautiously emerging of a distinct immune-inflammation landscape that could possibly be utilized to address these disparities.

Using a nested case-control study design, a positive association has been found between circulating plasma inflammation markers IFNλ, IL-12/IL-23p40, IL-6, IL-8 and C-reactive protein and a lung cancer diagnosis. However, data from this study does not support the utility of these associations in risk stratification [70]. Continuing this line of inquiry, elevated inflammatory mediators were also associated with having lung cancer. Levels of the mediators were distinct by population group and may offer clinical utility as biomarkers of disease [71]. The study described inflammatory proteins that were commonly associated with lung cancer in EAs and AAs (CRP, IL-6, IFN-γ and IL-8), but also inflammatory proteins that were distinct to population groups with SAA, sTNFRII, and CXCL9 associated with lung cancer in EAs only and IL-1β, IL-10, IL-15, IP-10, MIP-1α, MCP-4 and TNF-β associated with lung cancer in AAs only. The results were not driven by genetic ancestry or menthol cigarette use and ultimately, the origin of this inflammation-lung cancer association is still to be determined. However, IL-6, IL-15 and MCP-4 were identified as potential biomarkers of early-stage lung cancer. The observation may have important clinical utility and should be validated prospectively because biomarkers to differentiate between benign and malignant nodules are lacking in lung cancer. Suitable biomarkers are needed with urgency, particularly by AAs who are at highest risk of lung cancer. Targeting IL-6 is one option that may be worth exploring further (Figure 3).

Figure 3:

Anti-IL-6 therapy as an example to potentially reduce cancer outcome disparities through an immune therapy approach [33, 45, 71, 85].

Despite recent updates to the United States Preventive Services Task Force screening guidelines, expanding eligibility to include more AAs, current models suggest that although more lung cancer deaths in AAs will be averted, the disparity between EA and AA undergoing screening may not be targeted comprehensively [72]. Identifying and incorporating measurements of appropriate biomarkers that detect early-stage disease in AAs, in combination with low dose computed tomography which has a high rate of false positivity [73], could help minimize health disparities and improve patient outcomes in this population.

Aspirin use has been shown to reduce risk of non-small cell lung cancer in men only and was also associated with improved survival, but only among AA men and women [74]. Similar to previously outlined findings in prostate [64] and breast cancers [18], this points to racial differences in systemic inflammatory processes contributing to cancer progression which are being curtailed by aspirin use (Figure 1). It is unclear whether global genetic ancestry is an underlying factor of inflammation and the population-specific aspirin effect, or if other factors explain the prevalence of inflammation in AAs. Future studies that include participants of African ancestry should at a minimum explore how genetic factors, such as somatic mutations and functional polymorphisms, may modulate the response to aspirin.

For biological targets within the tumor, the global somatic mutation landscape is comparable in AAs and EAs, but AA lung adenocarcinomas are enriched for somatic mutations in PTPRT and JAK2 genes compared to EA tumors [75]. This is of interest because both genes are downstream signal transducers of the oncogene, STAT3, through cytokine and interferon signaling, and are potentially targetable with JAK inhibitors. Further work to determine immune response and inflammation by population group may offer opportunities to reduce disparities in lung cancer through targeting these pathways.

Colorectal Cancer

Distinct immunological landscape may contribute to poorer survival outcomes experienced by AAs compared to EAs

Significant disparities have been observed in colorectal cancer (CRC), following a comparable trend of increased incidence and mortality in men and women of African ancestry. Reasons for this disparity have not been studied to the extent of other cancers, but a more advanced stage at diagnosis, differences in treatment, lower screening rates, and differences in tumor biology are all believed to be contributors to the poorer outcomes for AAs [76, 77]. Additionally, among biological risk factors for CRC, obesity has been shown to contribute significantly [78], with AAs engaging in more high-risk CRC behaviors including being more likely to smoke, having reduced physical activity, and an unbalanced diet [79]. It is well known that obesity leads to inflammation, which can initiate and exacerbate cancer development. Obesity-related inflammation may also contribute to racial disparities in CRC incidence and mortality through changes in tumor immune response.

Recent studies comparing AA and EA CRC patients have revealed distinct immunological landscapes that may contribute to the poorer survival outcomes experienced by AAs. A more immunosuppressive environment has been described in preinvasive colorectal lesions from AAs as compared to EAs. Differences related to interferon signaling were also described by these authors where AA patients had lower densities of cells labeled with IFNγ [54]. Another recent study showed tumor-related differences in the interferon regulatory factor (IRF) family of transcription factors, key players in the interferon signaling pathway, where IRF3 and IRF7 were upregulated in adenocarcinomas as compared to normal tissues and were significantly associated with poor prognosis [80]. These and other studies suggest potential prognostic value in interferon-related biomarkers in not only colon cancer, but breast, prostate, and lung cancers, with particular importance in the tumor biology of AA patients. Additionally, as significant differences in interferon-related gene expression have been observed between population groups, developing therapeutics targeting these proteins and their signaling pathways may help ameliorate the increased mortality burden for populations of African ancestry, as they more often develop aggressive cancers.

Other investigations into population differences in the immune microenvironment in CRC have described an immunologically “cold” tumor microenvironment in AA patients, including reduced density of cells labeled as CD4+ T-cells, NK cells, Th17 cells, and mast cells, indicative of reduced effector cell activity in AA lesions [54]. Similarly, reduced numbers of macrophages and CD8+ T-cells, but increased numbers of B-cells, have been reported in AA tumors compared to EA tumors [81]. Interestingly, this T-cell suppression tumor environment can also be observed in AA women with ER-negative breast tumors in the form of a distinct T-cell exhaustion signature, which is associated with poorer outcomes in this population. Further studies into this signature in CRC patients is warranted and if found, may partially explain differences in mortality between AAs and EAs. With an increased understanding of immune profile differences between AA and EA CRC tumors, we can leverage this information for the development of targeted therapeutics to reduce mortality in overburdened population groups.

Concluding Remarks

Outcome disparities in certain major cancers that impact underserved populations have been recognized and studied for many years. While thought to be enhancing risk of lethal disease, the immunological and inflammatory differences in cancer biology between population groups described in this review may also offer valuable opportunities for precision therapeutic strategies to address these disparate outcomes. In the tumor, the increased presence of an immune-inflammation signature could be targeted by therapeutics in current development (e.g., ADAR1 inhibitors, NOS inhibitors together with taxane chemotherapy). However, it is important to recognize the prohibitive expense of novel treatments such as immunotherapy, which are out of reach for many patients from underserved groups who often do not have access to adequate healthcare and health insurance.

Furthermore, beyond the immediate tumor, differences in levels of immune cell types, inflammatory proteins, and cytokines in the tumor microenvironment and circulation show potential as biomarkers to guide interventions and disease targets. Inhibition of elevated platelets and platelet-derived factors, including COX-1/TXA2, using NSAIDs highlight a potential strategy against metastasis through targeting systemic inflammation (See Outstanding Questions).

Outstanding Questions.

• How can we apply a precision medicine approach to reduce cancer outcome disparities that target the tumor immune environment?

• What is the contribution of the immune-inflammation environment in tumors of African American patients to cancer outcome disparities? If we target this environment, can we reduce the excessive cancer mortality in this patient group?

• What are the causes of the distinct immune-inflammation signatures that associate with cancer biology in certain populations but not others?

• Do tumors traditionally considered “cold” deserve another shot at immunotherapy? Prostate, colorectal and breast cancer (ER- subtype) have shown elevated immune response. Could immunotherapy alone or in combination with other treatments be advantageous to patients with elevated immune activity, such as African American men with prostate cancer?

• How can CD8+ T-cell exhaustion signatures, recently characterized in African American breast and colorectal tumors, be leveraged to improve cancer outcomes in populations of African ancestry?

• Why do African American men with prostate cancer respond more robustly to the cancer vaccine, Sipuleucel-T?

• Why do African American men with prostate cancer respond more robustly to aspirin as a strategy to prevent mortality? Is inhibition of platelets by aspirin responsible for this observation. Do African American men with higher platelet counts respond the best to aspirin treatment?

• How does the social environment contribute to the increased burden of cancer-promoting systemic inflammation and immune deficiency in underserved populations?

• How can we ensure equitable access to clinical trials evaluating immune therapies? Should trials be mandated to recruit from population groups representative of the population being served by the clinical trial site?

Emerging single-cell sequencing technologies will further allow us to identify characteristics of immune sub-populations in cancerous tissues with a greater resolution, moving forward our efforts in precision medicine by better tailoring cancer treatments to the tumor microenvironment, with an aim of improving outcomes in patient groups that have long suffered from excessive cancer mortalities.

Lastly, participation of AAs in clinical trials has historically been low with AA women having an 11-fold lower participation rate compared to EAs [82]. Closing this participation gap may lead to advancements in cancer immune therapeutics, benefiting AA and other patients but with an impact on reducing cancer health disparities. While the reasons for this gap in trial participation are multifactorial, including historical mistrust of the medical profession due to major ethical breaches in the past, a higher prevalence of comorbidities, and a lack of access to academic medical centers involved in trials, the issue needs to be immediately addressed through tailored recruitment efforts to ensure generalizability of trial observations across population groups and equitable access to cutting-edge treatments [83, 84].

Highlights.

• Immunological differences in tumor biology, immune response and systemic inflammation between population groups are contributing to a population-specific disease etiology in many major cancers. These differences may contribute to the cancer disparities experienced by people of African descent.

• Treatments targeting systemic inflammation and immune response, such as aspirin use for cancer prevention and the use of cancer vaccines, such as Sipuleucel-T, may show increased efficacy in African Americans.

• The immune modulatory and metastasis promoting function of platelets can be targeted using NSAIDs.

• Increased clinical trial diversity is required to comprehensively evaluate current and emerging therapies with respect to immune function and a chronic inflammatory environment. This may lead to better characterization of therapy response and adverse effects across population groups.