Non-self glycan structures as possible modulators of cancer progression: would polysaccharides from Cryptococcus spp. impact this phenomenon?

Abstract

Invasive fungal infections (IFI) are responsible for a large number of annual deaths. Most cases are closely related to patients in a state of immunosuppression, as is the case of patients undergoing chemotherapy. Cancer patients are severely affected by the worrisome proportions that an IFI can take during cancer progression, especially in an already immunologically and metabolically impaired patient. There is scarce knowledge about strategies to mitigate cancer progression in these cases, beyond conventional treatment with antifungal drugs with a narrow therapeutic range. However, in recent years, ample evidence has surfaced describing the possible interferences that IFI may have both on the progression of pre-existing cancers and in the induction of newly transformed cells. The leading gambit for modulation of tumor progression comes from the ability of fungal virulence factors to modulate the host’s immune system, since they are found in considerable concentrations in the tumor microenvironment during infection. In this context, cryptococcosis is of particular concern, since the main virulence factor of the pathogenic yeast is its polysaccharide capsule, which carries constituents with high immunomodulatory properties and cytotoxic potential. Therefore, we open a discussion on what has already been described regarding the progression of cryptococcosis in the context of cancer progression, and the possible implications that fungal glycan structures may take in both cancer development and progression.

Introduction

Humans, as any other animal species, are historically afflicted by pathogenic fungal-related infections [1]. The main reason involved in the urge to study these infections is the immune evasion capacity that this pathogen displays during its life cycle [2]. Fungi environmental diversity implies an array of intrinsic resistance mechanisms that contributes to fungal resistance to competitors, like free-living organisms, and to the diversification of structural patterns associated with fungal species [3, 4]. Therefore, many environmental fungal species can become pathogenic and are capable of causing opportunistic infections. Consequently, they acquire a higher proliferation rate in an immunocompromised host, subverting the immunological response, through the action of the fungal virulence factors, at a cellular level [5]. The most common examples of fungal infections causing severe public health issues are the infections caused by Candida albicans species, comprising the higher part of global mortality by fungal diseases [6]. Interestingly, C. albicans is a microorganism from the commensal human microbiota that colonizes the skin and mucous membranes. In immunocompromised hosts, this yeast can grow considerably, promoting a superficial infection [7]. Due to this opportunistic behavior, C. albicans yeasts can develop the late stages of its life cycle, causing the formation of invasive hyphae in the host’s tissues, as is the case of common infections in post-transplant patients, as well as in chemotherapy-treated cancer patients [8]. These susceptible populations are not only subjugated to opportunistic infections by commensal microorganisms as C. albicans, but by other environmental fungi as well, causing severe cases of invasive fungal infections (IFI). Major examples are Aspergillus fumigatus and the pathogenic species of Cryptococcus, such as Cryptococcus neoformans and Cryptococcus gattii [9, 10].

Invasive fungal infections and cancer

Much is still debated about the association between IFI incidence in individuals with either immune deficiencies or chronic diseases [11]. Therefore, studies started to associate socioeconomic features with chronic diseases and cancer progression, where urbanized countries possessed a higher incidence compared to others, a phenomenon explained by the hygiene hypothesis [12, 13]. During the early stages of immune development in a prevalent hygiene status, more self-reactive immune cell populations are accumulated instead of activated antigen-specific cell clones. Then, the immune system is conditioned to self-reactivity and immune regulation; therefore, the tumor progression ends up being facilitated when the urge of autoimmunity is privileged [14]. However, the oversight by public and private health systems in underdeveloped countries, with a higher incidence of neglected tropical diseases, gives rise to new questions about cancer susceptibility [15]. The hygiene theory is challenged in this increasing scenario of microbe-related pathologies modulating the immune response against or in favor of tumor progression [13].

Naturally, some viral infections interfere with the cell cycle and proliferation and may favor the development of cancer, just as some bacterial infections, by promoting inflammatory processes, contribute to the necrosis of metastatic cells by a different mechanism. Naturally, some viral infections interfere with the cell cycle and proliferation and may favor cancer development [16]. Bacterial diseases, on the other hand, whether by inducing inflammatory mediators or directly by endotoxin production, may contribute to cancer cell necrosis [17, 18]. Furthermore, Candida albicans can also induce oral tumor progression by endogenous production of nitrosamines and release of its virulence factor, candidalysin, during infection [19, 20]. Therefore, microbial virulence factors such as endotoxins and other soluble molecules can modulate tumor progression. Furthermore, the presence of chronic infections implies epigenetic modifications that cause activation of oncogenes and inactivation of tumor suppressor genes [21]. Gastric cancer may be induced by Helicobacter pylori infection due to changes in DNA methylation, for instance [22]. Indeed, recent data suggests specific commensal fungal microbiome may be related to different types of cancer, such as pancreatic, breast, and ovarian cancers [23, 24]. Nonetheless, little is clear about the influence of IFI during oncogenesis.

Cancer patients are especially vulnerable to fungal infections for many reasons. The use of corticosteroid promotes a state of immunosuppression during their treatment [25], leading to a reduction of the host defense against infections, even promoting microbiota dysregulation [26]. The state of dysbiosis within membranes can lead to mucositis, facilitating the settling of pathogenic microorganisms [27]. Besides that, cancer chemotherapy generates a great metabolic stress and a severe immunity impairment. Therefore, cases of myelosuppression and mucous membrane ulcerations are frequently responsible for the entry of opportunistic fungi [28]. When it comes to IFI in cancer patients, a critical factor resulting in greater disease severity is the lack of control in the early stages of infection that quickly advances to graver forms, as the case of fungemia caused by C. albicans and meningoencephalitis caused by pathogenic Cryptococcus spp. [29]. IFI worsen rapidly in the more advanced stages of the infection. In addition, they tend to require prolonged use of antifungal treatment. Therefore, a late diagnosis makes it difficult to resolve the infection [30]. Furthermore, antifungal therapy may result in acute hepatotoxicity and nephrotoxicity during prolonged treatment [31–33]. The combination of different types of medication (antifungals and chemotherapeutic agents) can potentiate toxic effects, because they share the same metabolization pathways or because individuals are already metabolically debilitated by cancer [34, 35].

Although not a new idea [36], more significant associations between IFI and cancer have been made recently, concerning the synergic and deleterious potential that both diseases can bring about [37]. Previous works associate the increase of metastatic potential of some types of cancer caused by opportunistic infections by C. albicans [38, 39], such as hepatic carcinoma [40, 41], and oral squamous cell carcinoma (OSCC) [42, 43]. The argument that supports this mechanism is still not fully understood, and it may be related, in the case of C. albicans, with the invasive potential that the Candida hyphae possess, leading to cell–matrix destabilization and upregulation of the epithelial-mesenchymal transition (EMT) markers [42]. This may be related to the fact that C. albicans is potentially capable of nitrosamine production, a carcinogen associated with the development of oral squamous cell carcinoma (OSCC) and other types of cancers [19]. Inquiringly, some rare associations of patients developing OSCC after C. albicans infection have been observed [43]. It is worth mentioning that much is still discussed about the real reasons why potentially pathogenic fungi can enhance or trigger metastatic processes in humans. It seems to be due to a combination of the inflammatory status and mechanisms initiated by virulence factors intrinsic to pathogenic fungi, such as acetaldehyde [44], candidalysin [45], or acid aspartyl proteinases [20].

Cryptococcosis during cancer progression

Cryptococcosis is an invasive opportunistic infectious disease, caused by the pathogenic species of the Cryptococcus genre, and it is frequently associated with severe cases of pulmonary infection in cancer patients [46]. Despite the suggested evidence that cryptococcosis has the potential to contribute to the worsening of the host’s health status during cancer progression [47], the mechanisms involved in the relation between cryptococcosis and tumoral progression are still poorly understood. The majority of the cases reported are associated with the Cryptococcus neoformans species, known to infect immunocompromised hosts [1], while for other species such as Cryptococcus gattii, the association is still scarce [48]. Interestingly, cryptococcosis more commonly affects patients suffering from hematological malignancies than those bearing solid tumors [49]. The immunomodulatory potential of the Cryptococcus spp. during the infection is vastly explored and well described [50–54]. Most effects are associated to its main virulence factor, the foremost capsular polysaccharidic components, namely glucuronoxylomannan (GXM) and glucuronoxylomannogalactan (GXMGal). Both polysaccharides are capable of modulating the cell activation process and inflammatory response, with GXM being the most prevalent in the total capsule composition [55]. Interestingly, during cryptococcosis, these components with elevated immunomodulatory potential are constantly leaked by the fungus, permeating the host’s tissues. Therefore they have the capability to modulate the immune response in sites non-adjacent to the focal infection, acting systemically [56]. Although C. albicans infects primary sites of tumor progression, as occurs during OSCC, an IFI does not necessarily install itself at the same site as the neoplastic formation. As in the case of infection by Cryptococcus spp., which most often starts as a pulmonary infection, however, the vast bioavailability of its capsular polysaccharides with a high immunomodulatory effect has the potential to modulate other sites systemically and may not be limited only to the lung site [57, 58]. Some cases of coexisting Cryptococcus spp. infection with cancers, for instance, in the development of cryptococcoma together with pulmonary cancer [59], or even the treatment of breast cancer with anastrozole favoring the progression of cryptococcosis [60], point to some connection between tumoral treatment and infection progression. The relationship between Cryptococcus spp. and cancer goes both ways and breast or prostate cancer even in initial stages can facilitate cases of opportunistic infections in- and off-site [61–63]. The cryptococcal infection is very frequent in patients with acquired immunodeficiency syndrome (AIDS), with focal infections colocalized with the lesions caused by the Kaposi sarcoma [64]. Lymphoproliferative neoplasms are associated with Cryptococcus spp. infections as well [65, 66]. Furthermore, because of the incapacitated status of cancer patients, cases of Cryptococcus laurentii infection has been observed. This can lead to very worrisome implications, as C. laurentii is commonly seen as an environmental fungi species not associated with infections. Therefore, cancer patients may be affected by infections caused by previously non-pathogenic fungi [67, 68]. It is possible to speculate that fungi with the ability to evade the environment can be categorized as opportunistic fungi.

Anticryptococcal treatment and cancer chemotherapy

Chemotherapy in cancer patients tends to immunologically weaken the individual, which makes them susceptible to various opportunistic infections, such as pulmonary IFI [69]. There is a high mortality rate associated with IFI in cancer patients; therefore, treatment with antifungal drugs is mandatory in the early stages of diagnosis to increase survival [70]. However, antifungal prophylaxis is extremely limited in terms of diversity and availability of drugs, being limited to a few drug classes [71]. The infection occurrence is mainly due to chemotherapy, which compromises CD4⁺ T lymphocyte count levels along with defects in T helper lymphocyte function. Therefore, patients who develop AIDS are extremely susceptible to cryptococcosis [72]. In antifungal therapy against cryptococcosis, the therapeutic strategy consists of a combination of drug classes. Azole compounds and antimycotic polyenes are the most widely used and indicated by international guidelines and organizations, such as Food and Drug Administration (FDA) and German Society for Haematology and Medical Oncology (DGHO) [70, 73]. These ergosterol synthesis inhibitors are fungistatic agents that compromise the structural integrity of the pathogenic yeast [74]. First, therapy with flucytosine and amphotericin B is started, followed by continuous treatment with fluconazole for 10 to 12 weeks [75]. Alternatively, posaconazole, voriconazole, and itraconazole can be used. However, the most efficient in reducing the yeast’s levels in the cerebrospinal fluid is fluconazole [76, 77]. It is important to note that the use of azoles during chemotherapy should be taken with caution, since the prolonged administration of this drug class can lead to an excessive increase in the bioavailability of certain chemotherapeutics, thus leading to the potentiation of the deleterious effects of chemotherapy. The main reason for those effects is due to the fact that azole compounds are inhibitors of the hepatic enzymes of the cytochrome P450 3A4 complex (CYP3A4) and many chemotherapeutics pass part of their biotransformation route through this enzyme complex [78]. Ibrutinib, midostaurin, sorafenib, and venetoclax, for example, rely upon CYP3A4 for their metabolization and are highly impacted by the action of azoles, with their recommended dose being reduced when used in combination with these antifungals, and it is also recommended that serum levels of chemotherapeutic agents should be monitored continuously [79]. Therefore, this interaction can impact the effectiveness of chemotherapy, as well as immunological aspects, culminating in a worse prognosis for fungal infections. Due to the impact on the biotransformation of hepatic metabolites, not only are chemotherapeutic compounds affected, but the synthesis of endogenous hormones is also compromised with prolonged azole treatment [80]. Adrenal insufficiency is characteristic in this case, resulting in reduced production of endogenous steroids, since ergosterol is an essential precursor for the synthesis of many glucocorticoids, mineralocorticoids, and human gonadal hormones [81, 82]. This condition can lead to further debilitation of the individual and may even go unnoticed, since the cancer progression itself causes symptoms similar to adrenal insufficiency, such as weakness, anorexia, nausea, and vomiting [83]. Interestingly, treatment with ketoconazole and fluconazole is used in Cushing’s syndrome in order to reduce the high glucocorticoid hormone levels associated with this pathology [81]. In this context, renal failure is critical because concomitant treatment with anticancer agents in these patients becomes more toxic for individuals with lower renal clearance [84]. The effect of hormonal imbalance generated by adrenal insufficiency conditions the individual to an immunosuppressed state, mainly affecting populations of cytotoxic T lymphocytes such as the natural killer cells, which directly corroborates the impairment of antitumor immunity [85]. The strong hormonal modulation of azole compounds in the context of cancer has not yet been evaluated with care and detail; however, it is important to emphasize that hormonal disorders not only strongly modulate immune aspects, but also cancer progression and malignancy aspects [86, 87]. Also, many tumors respond directly to gonadal hormones. Breast cancer progression and malignancy can be greatly modulated by the presence of estrogen [88, 89], while prostate cancers respond to circulating testosterone levels, to a point where gonadal deprivation to reduce hormone levels to a castration level is an actual therapeutical option in some cases [90, 91]. Testosterone replacement therapy remains a controversial topic for hypogonadal men suffering from prostate cancer or even at a higher risk for it [92]. Taking this into account, any effects azole treatments for cryptococcosis can exert on hormonal modulation may lead to potentially significant repercussions on tumor progression and malignancy. Also, a higher risk for squamous cell carcinoma (SCC) has been associated to use of voriconazole [93–95]. Although the specific mechanisms involved are not yet known, one possible explanation might be linked to its main metabolite, a chromophore for UV-B radiation. The increased absorption of amount of ultraviolet (UV) light plays a key role in enhancing DNA damage [93]. Voriconazole is also capable of inhibiting vitamin A (vit A) metabolization and increasing the half-life of molecules such as tretinoin, leading to increased phototoxicity [96, 97]. Higher intake of vit A itself is associated with lower levels of ovarian and breast cancer, however. So, it is not a clear-cut relationship [98, 99]. It is clear, however, that chronic use of azole compounds can further enhance cancer progression if used inappropriately and without surveillance.

Repurposing of antifungals for cancer chemotherapy

Despite the metabolic stress that azole antifungals can cause in patients with concomitant chemotherapy for cancer treatment, the possibility of repurposing antifungal drugs in order to use them as adjuvant therapy in the treatment of certain types of cancer has gained traction in recent years [100–102], such as miconazole in osteosarcoma [103], terbinafine in promyelocytic leukemia [104], ketoconazole in colorectal and hepatocellular carcinoma [105], and itraconazole in cutaneous squamous cell carcinoma [106], melanoma [107], and glioblastoma [108]. Many antifungals act through compromising cell wall structure, enhancing DNA damage, or inhibiting mitosis, and many of these effects, apart from those directed at the cell wall, are similar to the action mechanisms displayed by chemotherapy drugs against malignant cells [109–111]. Therefore, the use of non-cancer drugs such as antifungals not only has theoretical justification for their off-label use [112, 113], but has also shown promise in oncological clinical trials [114]. In the case of azole drugs, activation of apoptosis pathways is one of the proposed mechanisms to control tumor progression [115]. Itraconazole has even been described as an inducer of a cell death pathway by inducing autophagy of metastatic cells, increasing the survival outcome in patients with colon cancer and glioblastoma [108]. Ketoconazole also elicits similar mechanisms in the context of hepatocellular carcinoma, while sertaconazole does the same in lung cancer [116, 117]. In addition to inducing cell death, the antiangiogenic effect of itraconazole limits tumor progression, since angiogenesis is a crucial mechanism for the maintenance of newly formed tumor tissue [118]. In fact, its use has already been considered beneficial in the joint treatment of acute myeloid leukemia with chemotherapy [119]. Furthermore, the inhibition of one of the pathways for cell proliferation, the Hedgehog pathway, important for tumor progression, is suppressed by the action of itraconazole [120]. Interestingly, one of the mechanisms by which itraconazole acts is by inhibiting P-glycoprotein (P-gp), an efflux protein of the ABC superfamily associated with multidrug resistance (MDR) phenotype [121]. P-gp inhibition in tumors exhibiting MDR phenotypes can lead to resistance reduction, facilitating the action of other drugs [122]. Itraconazole is also capable of inhibiting the ABC transporters, CDR1/2 in fungal pathogens. ABC transporters, or ATP-binding cassette transporters, are primary active transporters that use energy from adenosine triphosphate (ATP) hydrolysis to fuel the transport of molecules across membranes of prokaryotic and eukaryotic cells against their electrochemical gradient [123]. Furthermore, they are essential for the uptake of nutrients for cellular metabolism and are crucial in exporting molecules present inside the cytoplasm; therefore, they compose in tumor cells an essential mechanism for drug resistance, because they behave like an efflux pump for chemotherapy drugs [124]. These proteins are associated with drug efflux, reducing the effective concentration in the cytoplasmic interior of the yeast, and are therefore linked to azole resistance [125–128] (Fig. 1). Concomitantly, the use of doxorubicin, a chemotherapy drug of choice, has already been described as a potent inducer of ABC transporters in C. albicans, increasing the levels of CDR1/2 proteins [129]. Similar observations can be made for P-gp and other ABC transporters in cancer models using either doxorubicin or other anticancer drugs [130–133] and it is possible to theorize that drug associations between itraconazole and anticancer drugs could represent a higher chance of eliciting ABC-mediated drug resistance. Thus, in addition to the implications that fungal infection may have on antitumor immunity, drug treatment itself can modulate the response to tumor progression.

Fig. 1.

The effects of antitumor and antifungal drug therapy on immunity during metastasis and proposed mechanisms for the interaction between the pathogenic fungus Cryptococcus spp. and its capsular polysaccharides during tumor progression. MMP, matrix metalloproteinase; EMT, epithelial-mesenchymal transition; ABC transporters, ATP-binding cassette transporters. Green arrows indicate activation and induction effects; red arrows indicate regulation and inhibition effects; gray arrows indicate proposed effects. Upside and downside arrows indicate respectively upregulation and downregulation of indicated factors

Anticryptococcal immunity and cancer interplay

The facilitated of Cryptococcus spp. entry in cancer patients through the lungs can lead to greater dissemination of the fungus systemically [48, 134]. There are structural factors such as mannoproteins that facilitate adhesion to the lung epithelium and greater interaction of the fungus with host cells [135]. The activation of macrophages in the pulmonary microenvironment is decisive for cryptococcosis control [136]. Naturally, the maintenance of an inflammatory profile with the Th17 cell activation and IL-6 production is responsible for the Wnt and NF-κB pathway induction, both pivotal for tumorigenesis through apoptosis regulation, a mechanism already associated with C. albicans infection [26, 42]. In the case of Cryptococcus spp. infection, the effect may vary according to the species. In infections caused by C. neoformans occurs an increase in the Th1 and Th17 profiles responsible for activating the Wnt pathway [137]. However, in infections caused by C. gattii, there is a considerable disfavor of the activation of responses associated with the Th17 profile; furthermore, the interferences in the Wnt pathway in C. gattii are still unknown [138]. Despite this possible mechanism for oncogenesis promotion during IFI, Cryptococcus spp. infections can subvert the cytokine microenvironment promoting immune regulation. Interestingly, Cryptococcus spp. infection initially induces Th1/Th17 cell profile activation and cell recruitment by IL-18 production [139]. Invariably, the production of IL-18 is closely associated with the activation of cytotoxic cells with the production of IFN-γ that mitigate the progression of tumors and autoimmunity [140]. However, chronically, Cryptococcus spp. promotes Th2 responses, strongly associated with IL-33 cytokine production [141–143]. This cytokine is not only responsible for the positive feedback for Th2 maintenance, but in association with the TGF-β production, it is linked to enhanced invasiveness of malignant cells’ chemotherapy resistance during tumor progression due to their capacity to initiate EMT programming [144–146]. Furthermore, the recruitment of regulatory cells such as M2 phenotype macrophages is frequent in pulmonary cryptococcosis [147, 148]. This macrophage subpopulation contributes to a worse prognosis in the context of tumors [149, 150]. The T cell profile modulation during cryptococcosis could be activated differently depending on the fungal strain or species, as seen by the C. gattii species promoting a more Th2-oriented profile induction with compromised Th1 response in comparison with C. neoformans species [138]. The differences are significant as well in the regulation of matrix metalloproteinases (MMP), also markers of the metastatic process during tumor progression. During lung infection, C. neoformans induces upregulation of MMP-3 and MMP-12, an effect not replicated for C. gattii infection [151] (Fig. 1). This strongly suggests the immunomodulatory profile promoted by different species of Cryptococcus is divergent. Not only that, but it implies concomitant infections in cancer patients could have different impacts on disease outcomes, depending on the pathogen.

Possible role of the Cryptococcus capsular polysaccharides during cancer progression

It is well established that glycosylation changes are a hallmark of both cancer cells [152–157] and infiltrating immune cells in the tumor microenvironment [158–160]. Over the last 10 years, our research group has demonstrated that alterations in both N- and O-linked glycan structures are able to influence the behavior of transformed cells, modulating events related to the EMT process and multidrug resistance phenotype [132, 161–166]. Although some epidemiological studies have already described a correlation between infections caused by different fungi and numerous types of cancer [167–171], it is not well known how the pathogen and/or its polysaccharide constituents may participate in metastatic events or the acquisition of drug resistance phenotypes, which today are the greatest obstacles faced in clinical oncology [172–176]. In addition to the infection itself, the major capsular polysaccharide of Cryptococcus spp., GXM, may have significant implications for tumor progression. The potential of GXM to recruit suppressor T cells has already been described [177], as well as the reduced leukocyte translocation between epithelial barriers [178]. These characteristics are complicating factors regarding the containment of tumors by immunity, especially when associated with reduced migration of phagocytes and subversion of the production of inflammatory mediators generated by GXM [179]. Therefore, the facilitation of transepithelial passage and modulation of cell containment in the inflammatory foci due to exposure to GXM within the course of the infection itself could modulate the tumor invasiveness response. The epithelium of the host’s blood barriers can also be modulated by the Cryptococcus spp. capsular content to enhance adhesion. Despite the mechanisms through which GXM reduces macrophage phagocytosis [180], inducing cell apoptosis [181, 182], reducing T cell activation [183, 184], and generating affinity with epithelial cells via interaction with the CD14 receptor [1], it is closely associated with facilitating the passage of yeast across the blood–brain barrier [185]. Therefore, the interaction of the yeast with the epithelium seems to be important for its effective proliferation. However, data relating the epithelium dynamics between brain or lung cancer and Cryptococcus spp. infection has not yet been evaluated. In addition, other factors such as the enhanced CD44 expression caused by the hyaluronic acid that recovers the capsule and binds to the epithelium facilitate the fungal dissemination between lung and brain areas [186, 187]. Interestingly, the CD44 is a characteristic maker of mesenchymal cells that during infection is imprinted in the epithelial cell phenotype. Nevertheless, the reduction of E-cadherin expression is also a EMT hallmark, and its expression is dampened in the lung epithelium during cryptococcosis by the capsular content to enhance transepithelial passage of pathogenic yeasts, resulting in fungemia [144] (Fig. 1). Therefore, this gives rise to the possibility of persistent EMT maker expression during chronic cryptococcosis, increasing the possibility of metastatic dissemination of already established tumors or the generation of newly formed neoplasms. The capsular polysaccharides from Cryptococcus spp. are, in general, known for their pro-apoptotic potential [53]. Much of this pro-apoptotic capacity tends to downregulate cell activity by the formation of apoptotic bodies that are signals for regulatory activity [188, 189]. In the context of infection progression, this mechanism can worsen the cryptococcal infection by promoting the killing of effector cells and reducing their function. However, when it comes to cancer progression, the pro-apoptotic capacity of the capsular polysaccharides of Cryptococcus spp. could have a double effect. The downregulation of immune cells could dampen the antitumoral immunity, enhancing cancer progression. But at the same time, capsular polysaccharides could just as well induce tumor regression or impairment by the same pro-apoptotic mechanism. Nevertheless, the induction of apoptosis by capsular exopolysaccharides of Cryptococcus sp. has already been observed in non-small lung cancer cells [190]. Despite the cytotoxic activity of these capsular contents, IL-10 production generated with GXM treatment has the potential to regulate the cytotoxic cells [191]. Therefore, it reduces the cellular immunity potential of a possible important antitumoral immune response during concomitant cryptococcosis and cancer, leading to a poor prognosis. Hence, the strong association of cryptococcosis with tumor progression locally and systemically requires further evaluation and study.

Conclusion

Overall, there is little information about the immunopathogenesis of cryptococcosis associated with the progression of cancers, either in the possibility of the appearance of transformed cells or in the modulation of metastasis of pre-existing tumor cells and this relationship is still unclear. However, due to the great immunomodulatory potential that the infection and capsular factors exert on the infected host, it is very likely that the dynamics of tumor progression and metastasis can be influenced in some way in individuals affected with cryptococcosis and cancer, since other better-studied opportunistic fungal infections have a similar relationship with cancer progression. Nevertheless, promising antifungal drugs are being studied for off-label use in cancer treatment, leading to better patient prognosis. Evidently, the deleterious effect that an antifungal treatment in joint therapy with chemotherapy can bring to poor health patients should not be ignored, but rather increasingly studied to effectively implement the best strategies and care that must be taken in the tenuous balance between infection control and cancer chemotherapy.

An effort must be made in the field of cancer research to know more about the immune implications of a concomitant IFI, in order to unravel the possible effects of infection and its soluble virulence factors on tumor progression. Many questions still need to be clarified: whether the fungus and its capsular polysaccharides are involved in the EMT mechanism; whether the fungal infection modulates the glycophenotype of cancer cells; whether the promotion of oncogenes is associated with the development of systemic cryptococcosis; whether the infection itself can lead to metastasis of cancer cells, among other more elaborate issues. Obtaining answers to such questions will strongly contribute not only to better treatment protocols for cancer patients susceptible to fungal infections, but also to shed light on IFI that are neglected globally, and are responsible for high annual mortality rates, especially in oncological patients.

Author contribution

Conceptualization, Diniz-Lima I, da Fonseca LM, Freire-de-Lima CG, Freire-de-Lima L.

Technical support: Santos dos Reis J, Decote-Ricardo D, Morrot A.

Wrote the manuscript: Diniz-Lima I, da Fonseca LM, Freire-de-Lima L.

Figure elaboration: Diniz-Lima I.

Supervision: Previato JO, Mendonça Previato L, da Fonseca LM, Freire-de-Lima CG, Freire-de-Lima L.

Project administration: Freire-de-Lima L.

Funding

This work was supported by the Brazilian National Research Council (CNPq), the Brazilian Cancer Foundation, and the Rio de Janeiro State Science Foundation (FAPERJ).

Data availability

Not applicable.

Declarations

Ethical approval and consent to participate

Not applicable.

Consent for publication

All authors have read and agreed to the published version of the manuscript.

Conflict of interest

The authors declare no competing interests.