Oral cancer immunology: state of the art and future perspectivesAbstract
Oral cancer is a multifactorial disease involving genetic, epigenetic, and environmental factors. The literature indicates that inflammatory cells at the advancing front of the tumor induce a host immune response, preventing the spread of the tumor. However, cancer cells adopt various continued strategies to circumvent this immune surveillance. The complexity of immune mechanisms suggests that there must be virtually individual patterns of anti-tumor immune responses. Due to this important interaction of cancer with the immune system, the objective of the present study was to provide an up-to-date overview of immuno-oncology focused on oral cancer, summarizing the basic immunology, the classic risk factors, immunotherapy, and future treatment and prognostic perspectives.
Mouth Neoplasms; Carcinogenesis
Introduction
Since the beginning of the 20th century, Coley and Ehrlich theorized that the immune system could represent a potential “controller” of malignant tumor development.1 However, it wasn’t until the 1960s that Klein and Burnet showed that tumor cells have different antigens than healthy cells, supporting the theory of anti-tumor immunosurveillance.2,3 The accumulated evidence showing that immunocompromised individuals were at higher risk of developing malignant neoplasms and the discovery of natural killer (NK) cells in the 1990s helped strengthen the theory of immunosurveillance.4,5 Nevertheless, this theory left one question unanswered: Why can immunocompetent individuals also develop cancer?
The process of evading the anti-tumor immunological control is not limited to tumor development. It is a continuous mechanism of tumor “sculpting”, guaranteed by the tumor’s genetic instability, in which the better adapted and less immunogenic cells are selected with the goal of evading immunological control and favoring tumor progression. This process has been defined as “tumor immunoediting”, a much sophisticated role of the immune system in tumor dynamics, which restricts and shapes neoplastic growth, resulting from the recognition that the immune system in immunocompetent individuals can alter tumor immunogenicity. The immunoediting theory consists of three Es that lead to tumor progression from Elimination, to Equilibrium, and finally Escape6. The elimination phase is what is known as immunosurveillance, where the immune system destroys susceptible tumor cells. In this phase, cells from the innate system are recruited by stimulating inflammatory signals caused by tissue micro-ruptures from tumor growth. The production of stimulatory cytokines attracts more antigen-presenting cells, which migrate to the lymph nodes for lymphocyte stimulation. Then, tumor-specific CD4 and CD8 T cells production (adaptive system) begins. In the equilibrium phase, tumor genetic instability allows immunoselected clones to persist. This period is believed to be the longest and may take years for a clinically visible neoplasm. The escape phase is the clinical detection stage, when the proliferation of immunologically selected clones becomes uncontrollable, and the tumor is clinically apparent.
The presence of immune cells in the tumor microenvironment (TME) leads to the pre-definition that cancer is also an immune-mediated disease, in addition to its genetic basis. Tumors can organize an immunosuppressive microenvironment that is dependent on reciprocal interactions between tumor and host. Tumors are not only affected by the surrounding tissues, but also affect adjacent structures by corrupting and recruiting non-malignant cells into an area, thus forming the TME. Nowadays, it is understood that the tumor is not only a mass of cells that grows in an unrestrained way, involving structures over time, but it contains stromal and several immune cells, which are collectively denominated tumor-infiltrating lymphocytes – TILs – despite not being formed exclusively by lymphocytes. Numerous cytokines participate in this process, promoting the survival of tumor cells and the development of neoplasia. A recent meta-analysis identified a higher concentration of cytokines IL-8, IL-6, TNF-α, IL-1β in saliva of the oral cancer group compared to individuals without lesions or with potentially malignant oral disorders.7 This resembles the functioning of a “mini organ”, in which the various cells, elements and substances that make it up interact and collaborate with its support, allowing the progression of the neoplasm (Figure 1).
Due to the complex interaction between cancer and immune system, our objective was to provide an updated overview on immuno-oncology focused on oral cancer. We will travel through the elements of the TME and attempt to provide knowledge about the basic immunology of each cell type observed in clinical practice, passing through the classic risk factors, immunotherapy, and future perspectives of treatment and prognostic mapping.
TME Components Interrelated with Immune Mechanisms
Tumor-infiltrating lymphocytes
The pattern of conversion and dominance of suppressive or inflammatory TIL appears to mark the global anti-tumor response. Longer disease-free interval and overall survival were associated with TIL with CD4+ and CD8+ predominance in head and neck cancers.8 Subsequent studies showed that not only the pattern of TIL infiltration was important, but also the proximity to the tumor and tumor topography.9,10 Patients with a CD3+ T lymphocyte infiltrate closer to the tumor within the TME of head and neck malignancies, including multiple topographies, had better outcomes, whereas a peripheral stromal infiltrate showed no association with prognosis (Table).9
Many proposals have been suggested to assess the immune response in oral cancer. One of the most promising for prognosis of early stage tongue cancers was proposed by the team led by Dr Almangush and colleagues, based on assessment of TIL and tumor-stroma ratio.11 Categories with predominance of TIL over stroma are considered low risk.
A recent meta-analysis stratified TIL into CD4 and CD8+. CD4+ infiltrate showed an inverse relationship with mortality in oropharynx cancer but did not present statistical significance for oral and hypopharynx cancers. CD8+ showed an inverse relationship with mortality in oropharynx and hypopharynx cancers but did not show statistical significance in oral and larynx cancers.10 Moreover, a meta-analysis evaluating the prognostic impact of TIL in oral cancer showed that high infiltration of CD8+ T cells, CD68+ macrophages, CD57+ NK lymphocytes, and CD45RO+ memory T cells was associated with better overall survival, while marked infiltration by CD163+ macrophages was associated with poor global survival.12 Stroma formed by some subtypes of macrophages, dendritic cells, NK cells, CD8+ T and CD4+ Th1 T lymphocytes tends to provide an environment that responds better to checkpoint inhibitors, especially anti-PD-L1 (programmed cell death).13 Lower infiltration of T-CD8 lymphocytes into tumor areas in patients with oral cancer was associated with lower recurrence-free survival and increased risk of distant metastasis.14 Survival models that included CD8+ T lymphocytic infiltrates were able to improve the prediction of specific survival compared to the current UICC (Union for International Cancer Control) -TNM pathological stage model.14
T CD8+ lymphocytes
CD8+ T lymphocytes are directly involved in the release of cytotoxic molecules and in the production of regulatory factors capable of stimulating other players in the immune system. T cells are part of the adaptive immune system and depend on activation by other cells, usually antigen-presenting cells (APCs).15 The T cell receptor (TCR) of CD8+ T lymphocytes has an affinity for major histocompatibility (MHC) class I. Cytotoxic T cells that react to self-antigens presented via MHC-I are eliminated in the process of immunological tolerance. Those that react to non-self-antigens survive and proliferate in tissues, as a way of organizing anti-tumor resistance and defense against harmful microorganisms. During the MHC-I/TCR interaction, activation of CD8+ T cells can occur through the interaction of the CD28 receptor with CD80 (B7-1) or CD86 (B7-2/B70) ligands present on the surface of dendritic cells or via the Fas ligand, directly interacting with Fas/CD95 receptors on tumor cells. This signal can be replaced by cytokines released by CD4+ helper T cells.15
Since cytotoxic T lymphocytes are one of the pivots of effective anti-tumor control, they have been the target of research focused on the shift in TME to an immunostimulatory profile. One of the most successful modalities of immunotherapy is the checkpoint receptor inhibitor, which will be discussed in the following paragraphs. Other targets are costimulatory receptors, sometimes in protocols combined with checkpoint inhibitors.16
In head and neck cancer, there are interesting studies with the use of curcumin in animal models. Curcumin use has been associated with reduced expression of PD-L1, PD-L2 and Galectin-9 in head and neck cancer, restoring the ability of cytotoxic CD8+ T cells in mice with induced oral cancer. Curcumin increased the proliferation of T cells, TILs, and anti-tumor cytokines and reduced the expression of PD-1 and TIM-3. Furthermore, it was associated with the expression of CD4+CD25+FoxP3+ T reg cells.17 Because of the invigorating effect on the immune system at different levels, curcumin might be an interesting adjuvant to well-established therapies for head and neck neoplasms.
T CD4+ lymphocytes
CD4+ T cells (T helper lymphocytes) belong to a heterogeneous group of cells whose function depends on the type of cytokine they produce. Th1 produce IFN-γ, IL-2, and TNF-α, playing a role in anti-tumor cellular immunity by stimulating CD8+ T lymphocytes. Additionally, they promote the expression of CXCL9 and CXCL10 in the TME, increase the expression of MHC class I and II on the tumor surface, and promote the polarization of macrophages towards the M1 phenotype. Th2 cells produce IL-4, IL-5, and IL-13. In the context of cancer, their action has already been described as ambivalent, although, in humans, infiltration of T cells with a predominance of the Th2 phenotype is generally associated with a worse prognosis.18 Th17s produce IL-17, IL-21, and IL-22. Like Th2, their presence has been reported to be associated with both a good and a poor prognosis.18
Treg lymphocytes
Treg cells are classically recognized for their role in preventing autoimmunity by expressing CD25, CTLA4 (cytotoxic T lymphocyte-associated antigen-4), and CD39 on their surface. Among other actions, they inhibit the action of NK cells, dendritic cells, and B cells, being associated with immunosuppressed states in the context of head and neck cancer.19 However, controversial evidence associating the presence of Treg and joint expression of FOXP3 with better prognosis has raised the probability that Treg cells act in a polarized manner.19 In oral cancer studies, the monotony in the use of markers for Treg research, mostly nonspecific, together with the heterogeneity of the studied populations and recruitment criteria, could lead to inconsistent results.20
Tumor-associated macrophages
Tumor-associated macrophages (TAMs) are one of the main leukocytic components of the TME in oral cancer. The predominance of M1 (anti-tumor orientation) or M2 (pro-tumor orientation) phenotypes in subpopulations of patients with oral cancer was associated with disease outcome. This has been evidenced by immunohistochemical markers associated with these phenotypes, such as CD11c (highly expressed, although not restricted to M1), CD163, and CD206 (M2). Increased CD163 levels were associated with worse overall survival, worse disease-free survival, higher recurrence rate, low cell differentiation, and lymph node metastasis in oral cancer. Likewise, higher levels of CD206 were also associated with more advanced staging, larger tumor diameter, lymph node metastasis, and lower specific survival in this group. Other studies with premalignant lesions showed a gradual evolution in the proportion of markers associated with TAM from hyperplasia zones, low- and high-grade dysplasia, and invasive carcinoma, indicating an involvement of macrophages in the evolution of potentially malignant lesions into cancer, depending on the predominant polarization of this population.21 However, while attempts to rebalance the polarization between M1 and M2 through targeted therapies have shown promising results in some solid organs, the results in oral cancer are limited.21
Dendritic cells
Dendritic cells are responsible for initiating the immune response. Along with macrophages, they are part of the APC group, promoting signals for the activation of T cells. Increased density of DC infiltrate in TME is associated with better prognosis and better response to anti-PD-1 therapy in many types of cancer. Tumors can modulate the presence and action of DCs in TME by reducing the expression of CCL4 on its surface and the production of PGE2, inhibiting its maturation, survival, and differentiation. The reduction of MHC-I expression on the surface of these cells, promoting the downregulation of T cells, is another known tumor evasion mechanism. In contrast, radiotherapy and some of the conventional chemotherapies (bortezomib, doxorubicin, epirubicin, idarubicin, mitoxantrone, and oxaliplatin) have the power to release factors resulting from cell death, capable of recruiting DCs to the TME. Therapies based on DC activation and mobilization are already a reality in the treatment of some tumors. Intravesical BCG, in the management of superficial bladder neoplasms, stimulates the viability and activation of DCs. Imiquimod, a Toll TLR7 receptor agonist, increases the inflammatory response at the expense of an increased DC infiltrate in the management of superficial skin carcinomas.22 TLR7 is highly expressed in oral squamous cell carcinoma. In vitro studies have shown that the growth of these cells can also be inhibited with imiquimod.23 More than 200 DC vaccine trials are available. However, the benefit of DC vaccines is limited, especially in patients with advanced disease, in whom they have usually been tested. One of the only approved DC vaccines is for advanced prostate cancer, with an added survival of about 4 months.22
Natural killer cells
Along with APCs, NK cells represent the main components of the innate immune response. They act as a first line of defense, eliminating targets without prior sensitization, through cytotoxic activity regulated by surface receptors. Not only have large numbers of NK cells been associated with better survival in oral cancer, but data from a recent meta-analysis also showed that, along with CD163+ M2 macrophages, CD57+ NK cells were the only statistically significant biomarkers and the best immunological prognostic markers found in that review.24 The activation of NK cells is regulated by a balance between inhibitory and excitatory signals, the former occurring mainly via NKG2A. NKG2D and other stimulatory cytotoxicity receptors, such as NKp30, are potent anti-tumor response activators. Exosomes released by tumor cells have been associated with overexpression of stimulatory pathways in NK cells in oral cancer cell cultures.25
NKT Cells
NKT cells are found at the intersection between innate and adaptive immune systems, expressing both NK cell and T cell surface markers. Their most notable property is their ability to produce substantial amounts of cytokines such as IL-4, IFN-c, and IL-12, being able to activate a variety of cells, including T lymphocytes, B lymphocytes, NK cells, and macrophages and to recruit dendritic cells, acting as a regulator of the immune response. In the anti-tumor response, NKT cells induce cytolytic activity through the activation of the TH1 stimulatory pathway. Three distinct phenotypes exist in humans: CD4+ CD8- (CD4+), CD4-CD8- (double negative; DN), and CD4-CD8+ (CD8+). Their frequencies are organ-specific and each of these phenotypes is associated with a pattern of antitumor response, a fact already observed among patients with oral cancer.26
Tumor-associated neutrophils
Neutrophilia and a high neutrophil/lymphocyte ratio have been associated with a worse prognosis in several types of cancer. In head and neck malignant neoplasms, the increased presence of TANs (tumor-associated neutrophils) proved to be an independent risk factor for recurrence and overall survival. TANs also have a differential activation status, suggesting pro- or anti-tumor patterns.27 The N1 profile is characterized by high levels of TNF-α, CCL3, and ICAM-1 and a low level of arginase, while the N2 phenotype is characterized by up-regulation of chemokines CCL2, CCL3, CL4, CCL8, CCL12, CCL17, CXCL1, CXCL2, IL-8/CXCL8, and CXCL16. In studies of head and neck cancer, greater infiltration of polymorphonuclear granulocytes in the tissue was associated with worse survival in patients with advanced disease.28 However, there is little evidence of the association between TANs and oral cancer.
Immune checkpoints
PD-L1 and PD-L2 ligands are predominantly expressed in APCs. They are part of a group known as inhibitory checkpoint receptors (ICRs), inhibitory receptors that act as “off switch” of the immune response. Their presence in healthy tissue suggests a role for these proteins in immune tolerance. Besides these, others are known, such as CTLA-4, T-cell immunoglobulin, mucin protein-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3)19 (Figure 2). Sievilainen et al. (2019) described in their recent systematic review 7 immune checkpoints associated with worse survival in oral cancer.29
Dendritic cell interacting with T lymphocyte, T cell receptor with MHC-II, and CTLA-4 checkpoint with the antibody (immunotherapy) blocking the brake system.
Through different mechanisms, tumor cells can increase the expression of PD-L1, for example, on its surface, blocking the activation of the immune system. PD-L1 is commonly found in NKT cells, B lymphocytes, activated monocytes, and dendritic cells, and can also be induced in CD4+ and CD8+ T cells.30 Although several inhibitory immunoreceptors have already been identified, PD-1/PD-L1 is the most successful “immune checkpoint”. It is the target of approved therapy for several different cancers, often associated with a durable response, although the overall response rate does not typically exceed 10–30% in most cases13 (Figure 3). Not all PD-L1 expressing tumors respond well to therapy. On the other hand, there are PD-L1-negative cases that respond to these agents, which shows the controversial role of PD-L1 expression in predicting response to checkpoint inhibitors.
T cell interacting with tumor cell through T cell receptor-MHC-I, and checkpoint PD-1 (T cell) and PD-1L (tumor) with the antibody in the middle (immunotherapy).
In 2018, Dr James Allison and Dr Tasuku Honjo shared the Nobel Prize in physiology and medicine for their work in the discovery of the checkpoint proteins CTLA-4 and PD-1, respectively, as well as their blocking mechanisms through the action of antibodies.31 Their work permitted the development of a number of immunotherapies in oncology that initially showed promise in patients with advanced melanoma and have since expanded to include practically all subsites of the aerodigestive tract.32
A recent meta-analysis evaluated the role of PD-L1 expression in the prognosis for patients with oral cancer. Although PD-L1 expression has been shown to be an independent prognostic factor in several types of cancer, this was not found to be the case among patients with oral cancer.33 One of the reasons for this may be the heterogeneity of the studies, as some of them mixed samples from biopsies and resections as well as tissue samples from different locations within the TME, and the gender differences in expression.33
Another recent study added a variable to this equation, showing that oral cancer patients with high expression of CD4+ and CD8+ TILs also exhibited a high expression of PD-L1.34 The authors did not find an association of a CD8+ infiltrate with overall survival in the sample, but only in specific subgroups. The authors justify that the pattern observed may reflect a resistance mechanism of the adaptive immune system. Maybe a natural brake to avoid exaggerated responses and autoimmune mechanisms.
Risk factors and role of immune mechanisms in the pathophysiology of oral cancer
In addition to its direct carcinogenic potential from cell damage, tobacco exerts an immunomodulatory action, reducing the capacity of dendritic cells to act in the anti-tumor defense, as well as their population in the TME.35 Likewise, it suppresses the Th1-mediated immune response, facilitating the generation of a Th2-mediated response, induces the overproduction of anti-apoptotic factors, impairs the phagocytic capacity of macrophages, and induces qualitative and quantitative defects in NK cells.36 Alcohol dehydrogenase (ADH) converts alcohol into carcinogenic metabolites and acetaldehyde, inducing a local inflammatory response, with increased production of reactive oxygen species, providing a favorable microenvironment for the promotion and survival of tumors.37 Smoking and alcohol consumption are also associated with the pattern of CD4+/CD8+ infiltrate in the TIL of patients with oral cancer, showing that consumption of these substances is not only associated with a carcinogenic role but also influences the anti-tumor immune response.34
In the same way, the areca nut induces the production of IL-6, TNF-α, PGE2, and prostacyclin by keratinocytes, suppressing the function of cytotoxic T lymphocytes and inducing CD4+ Th2 T lymphocytes by stimulating the synthesis of IL-4, IL-5, IL-6, IL-10, and IL-13. Furthermore, it can inhibit the phagocytic ability of APCs and the action of neutrophils. In the case of exposure to betel leaf (betel quid/betel leaf), it is believed that the induction of IL-6 production is one of the main mediators of the immunological part of the pathophysiology of the disease, although it is difficult to isolate the biases of exposure to other carcinogens when attempting in vivo studies.38
There is a discussion about the etiologic mechanisms of oral cancer in non-smoking and non-alcohol drinking patients. There is no evidence of HPV as etiological factor in this group of patients.39 Some authors have investigated exposure to environmental factors, including low intake of tea, fruits, and vegetables, recurrent oral ulcerations, passive smoking, and poor oral hygiene. There are studies showing a positive correlation between periodontal disease and oral cancer, signaling a possible inflammation route through the change of the microbiome.40 Apparently, the role of the microbiome does not seem to be restricted to the pathophysiology of disease, but it also participates in patient reactions to oncological therapies by modulating the toxicity of chemotherapy, radiotherapy, and immunotherapy.41
Immunotherapy
Immunotherapy is the third most important wave in the history of systemic cancer treatment, after chemotherapy, which dates back to 1940, and target therapy, which dates back to 1990. It is also known as biological therapy or biotherapy; the principle is to stimulate the immune system itself to fight cancer more effectively. There are several factors involved in immunotherapy, such as: a) monoclonal antibodies (directed at different targets); b) vaccines (form protein or cell); or c) non-specific agents (usually cytokines).42
The role of immunotherapy is to reactivate natural anti-tumor immunity. However, the explanation behind the lack of uniform response to this kind of treatment is not completely understood. Testing these drugs in treatment-naive groups would be interesting. Studies with neoadjuvant therapy in the oral cavity have emerged, still with small samples but with promising results. Volumetric shrinkage rates have ranged from 40 to 75% in initial studies, with no signs of impact on increased locoregional recurrence rates.30 The intratumor genetic heterogeneity may also contribute to poorer clinical outcomes and drug resistance. By exploring the genomes, insights into tumor-associated neoantigens, new biomarkers for driver mutations, and mutation signatures could also guide more effective immunotherapies.43
Problems, areas under development, and future potentials
The treatment of advanced oral cancer (the majority of T3 and T4) remains a challenge. Although immunotherapy has been a powerful weapon in the treatment of advanced head and neck cancer and is now the first choice for palliation in several subtypes, only 1% of Indian and African patients are estimated to have access to or use these therapies.44 Furthermore, the percentage of patients who respond to the main immunotherapies routinely used in head and neck cancer is still low, with an overall response rate of about 45%.45 About 1/3 of patients have post-treatment relapse, and the average increase in survival in comparative studies with what has been considered the gold standard therapy is only 4 months.46
One strategy explored for cancer treatment is photodynamic therapy (PDT). Its action combines the effect of a photosensitizer with laser and oxygen. The photosensitizer is light-activated and causes a series of photochemical and photobiological reactions, resulting in irreversible damage and eventual death of the target cells.47 The great advantage of using this technique is the possibility and safety of using it in combination with all other conventional therapy modalities used. Studies suggest that its action combined with CTLA-4 blockade may enhance the T-CD8+ cytotoxic response to ensure durable tumor eradication and induce immunological memory.48 PDT has been considered one of the therapeutic alternatives for initial or recurrent head and neck squamous cell carcinoma, and its combination with checkpoint blockers may change the course of the disease in the future.49
TIL patterns have been raised as a potential prognostic marker in several neoplasms, including those of the head and neck. However, the conventional way of manual inspection and counting of stained cells to assess the quantity and quality of biomarkers is highly observer-dependent and potentially error-prone. The introduction of automated digital image analysis has standardized and objectified pathological analysis.50 Although immune scores for oral cancer are still under development,50 they have already shown their value for prognostic prediction in colorectal neoplasia, for example.8 Advances in digital pathology may partially eliminate biases and enable the combined use of immunohistochemical markers and immunofluorescence tests in practice.
Conclusion
The complexity of immune mechanisms suggests that there must be virtually individual patterns of anti-tumor immune responses. The challenge will be to integrate the amount of information generated in cancer research for better management of these patients. As researchers, we tend to look for the answer in the collective bulk of information and data. However, it seems that this field will be increasingly dominated by personalized treatments.
Acknowledgments
This study was supported by the Coordination of Improvement of Higher Education Personnel (Capes, Finance Code 001), Brazil. L.F.S. is the recipient of fellowships. M.D.M. is a research fellow funded by the Brazilian National Council for Scientific and Technological Development (CNPq).
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