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 Table of Contents  
Year : 2022  |  Volume : 10  |  Issue : 2  |  Page : 73-79

Unraveling the significance of immune contexture in oral cancer

1 Department of Oral and Maxillofacial Pathology, Christian Dental College and Hospital, Ludhiana, India
2 Department of Endodontics and Conservative Dentistry, Christian Dental College and Hospital, Ludhiana, India
3 Department of Orthodontics, Desh Bhagat Dental College, Mandi Gobindgarh, Punjab, India

Date of Submission21-Apr-2021
Date of Acceptance29-May-2020
Date of Web Publication16-Nov-2022

Correspondence Address:
Deepti Sharma
Department of Oral Pathology and Microbiology, Christian Dental College and Hospital, Ludhiana, Punjab
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/DYPJ.DYPJ_22_21

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Numerous epidemiological and molecular biological studies have shown that inflammatory cells and cytokines in the tissues that surround tumors contribute to tumor development and progression. The immune response to tumors is complex, involves the interaction of several cell types of the adaptive and the innate immune systems, and has an important role in the progression of a variety of solid tumors. Tumor-infiltrating lymphocytes (TILs) have been studied as an indicator of tumor inflammation, and it has been reported that TIL subsets have their own roles in cancer progression. The differences in T-cell repertoire in different stages of cancer influence the prognostic and predictive response of the patient. Several studies have reported that CD3+ and CD8 + TILs are associated with good clinical prognosis in different cancer types including head-and-neck cancer, although contradictory reports are available regarding the role of CD4+ T-cells and + regulatory T-cells (Treg cells; forkhead box protein 3 [FOXP3] cells). This review is an attempt to elucidate the concept of immune infiltrate in oral squamous cell carcinoma to comprehend the role of immunoscore as an adjunct to tumor, node, metastasis staging to guide patient treatment. Immunoscore could provide an excellent setting for immunotherapeutic strategies to complement current standard chemoradiation and may benefit high-risk patients. We emphasize the need to standardize methodology, scoring criterias and also to develop validated cutoff values. Tumor aggressiveness and therapy resistance are influenced by the interplay between tumor cells and their microenvironment, only a better understanding of this will permit a rational design of new immunotherapeutic approaches.

Keywords: Biomarkers, immunotherapy, oral cancer, precision medicine, tumor-infiltrating lymphocytes

How to cite this article:
Sharma D, Koshy G, Sharma VK, Malik G. Unraveling the significance of immune contexture in oral cancer. D Y Patil J Health Sci 2022;10:73-9

How to cite this URL:
Sharma D, Koshy G, Sharma VK, Malik G. Unraveling the significance of immune contexture in oral cancer. D Y Patil J Health Sci [serial online] 2022 [cited 2023 Mar 24];10:73-9. Available from: http://www.dypatiljhs.com/text.asp?2022/10/2/73/361366

  Introduction Top

The ambiguity around cancer has remained undeciphered and from the past many decades, it still continues to haunt mankind. Despite emphasis on early screening and diagnosis, development of advanced molecular diagnostic and therapeutic techniques, GLOBOCAN 2018 worldwide, and Indian statistics are alarming and have barely improved for many cancers.[1] In developed countries, head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy, with over 600,000 new cases per year worldwide.[2] According to the India fact sheet of GLOBOCAN 2018, there is a huge 11.4% rise in the number of people suffering from lip and oral cavity cancer in just 6 years since 2012. The number of new cases of cancer of lip and oral cavity in 2018 are 16.1% and 4.8% in males and females, respectively.[3] Over 90% of oral cancer is constituted by oral squamous cell carcinoma (OSCC), which is locally invasive with aggressive growth pattern, cervical lymph node spread, and high morbidity and mortality rate presenting a significant challenge in conventional treatment options.[4] Current standard-of-care treatments including surgical resection, chemotherapy, and radiation have not been successful enough to improve 5-year survival rates which are still below 50%.

In recent years, the scientific community’s concept of HNSCC has changed dramatically from cancer cell biology-centric approach in particular genetics and cell-signaling mechanisms to dynamic tumor microenvironment (TME) and immune contexture as a tentative target.[6]

  Cancer Immunological Concept Top

Numerous studies published in the past few decades have shown that the changes in the inflammatory milieu in turn influence the evolution of tumors, invasion, and metastasis. Several cellular components of the adaptive and the innate immune systems play an important role in the progression of a variety of solid tumors, and immune response to tumor biology is very intricated.[7] TME is populated with multiple immunogenic cells including tumor-infiltrating lymphocytes (TILs), natural killer cells, macrophages, antigen-presenting cells, and myeloid-derived suppressor cells. The other cellular components and factors include cancer-associated fibroblasts, neutrophils, macrophages, platelets, mast cells and also various secreted cytokines, chemokines, growth factors, and proteins of the extracellular matrix.[8] Immuno-oncology branch is steadily proving its worth in many solid malignancies. The recent utility of immune-modulating agents as a therapeutic modality has proven the concept that immune system activation is efficacious in tumor elimination.[9] “Immune contexture” refers to the composition and the relative fraction of various immune cell subsets, their functional orientation and localization within the TME. Varying immunophenotypes have prognostic and predictive implications thus paving the way for a standardized, powerful immune stratification system.[10]

TILs are the key constituents of immune microenvironment, and lymphocyte infiltration into cancer tissue has been used as an indicator of local immune response and is considered as vital predictor of tumor biology and outcome.[11] TILs are now evaluated as readout markers for prognostication, treatment response of tumor as well as new scope for therapeutic intervention. Major subtypes of TILs include CD3+ T-cells (pan T-cell marker), CD4+ T-cells (helper T-cells), CD8+ T-cells (cytotoxic T-cells), and CD4+CD25+ regulatory T-cells (Treg cells; forkhead box protein 3 [FOXP3] cells).[12] Thus, quantifying and subtyping the TILs depict the immune response in the TME, facilitating either tumoral immune attack or escape and thereby affecting outcome. The constructive impact of the immune infiltrate with cytotoxic T-lymphocytes and memory phenotype has been shown in various solid malignancies including breast, colorectal, melanoma, ovarian, bladder, urothelial, esophageal, prostatic, pancreatic, cervical, hepatocellular, gastric cancers, and also head-and-neck cancer.[13]

Literature review reveals “high CD3 or CD8 expression on TILs as an independent factor for favorable overall survival (OS), local progression-free survival, and distant metastases-free survival.” However, contradictory results are available regarding relationship between CD4, FOXP3+ TILs, and prognosis.[7],[12] TILs also have been translated into a therapeutic agent in adoptive cell transfer-based treatments of cancer, mostly of solid malignancies.[14] Inflammation and immune cells are intimately associated with either tumor progression or suppression. The current research has therefore focused on identifying immune biomarkers to subdivide patients into clinically significant groups and to build up more effective targeted therapies.[15]

A series of complex inflammatory targets are implicated in the progression from potentially malignant disorders (such as oral leukoplakia and oral lichen planus) to OSCC, which have not been elucidated yet. Number of TILs, their phenotype, function, and location in the microenvironment of OSCC are significant and may differ by tumor site and extent. It has been found that in OSCC, “it is not only the number of CD8+ T-cells in the tumor that defined immune response and clinical outcome, but it is the location and relationship of the effector CD8+ T-cells to suppressive elements (FOXP3 or programmed cell death ligand 1–positive cells) in tumors that most consistently predicted survival.”[16] There is enough data collected till date to suggest that subtypes of HNSCC are clinically, histologically, and molecularly distinct. Yet, the treatment approach is uniform for different subtypes and with limited success.[17] In HNSCC, the need for enhanced treatment options is acknowledged because of poor survival rates and significant toxicities resulted by existing treatment strategies.[18] Therefore, elaborate knowledge of dynamic interaction between immune contexture and TME is critical for both selection of and reaction to treatment.[19] It is important to efficiently and accurately screen out specific biomarkers which could be accepted and implemented in clinical practice so that patients would be cured and lead a higher quality of life. Hence, to evaluate tumor receptiveness to immunotherapy and also to explicate the mechanisms of immune escape more reliable predictive biomarkers are needed [Figure 1]. In addition, identification of specific targets will aid in strengthening immunosurveillance and immunoediting.[20]
Figure 1: Tentative mechanisms of immune escape

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Conventional cancer classification tools include tumor staging and grading which involves assessment of various clinical and pathological parameters. The prognostic categorization provided by the tumor, node, metastasis (TNM) staging system has not been drastically improved by any gene or genomic signature in over 80 years.[21] However, the same stage tumors are diverse with respect to aggressiveness and treatment response. Thus, the prognosis can significantly vary among patients within the same histological tumor stage.[22] The advanced stage cancer can remain stable for a long time in few patients whereas relapse, rapid tumor progression, and patient death has been reported with approximately 20%–25% of TNM I/II stage patients, regardless of total surgical resection, no residual tumor burden or distant metastasis. It would have been better if we could do risk stratification of patients, especially based on immune profile, thereby improving adjuvant treatment selection. It would curb under/over treatment of patients and help avoid unnecessary toxicities without compromising outcomes.[23] The upcoming classification of cancer into immunogenic “hot” tumors and hypoimmunogenic “cold” tumors is an impending advancement in immunological context of tumors. Thus, biomarkers that consistently reveal the biological diversity of tumors are needed to strengthen the TNM classification for better tailoring the therapeutic decisions to the patient’s need and tumor behavior.[24]

  Immunoscore: Assessment Tool for Tumor-Infiltrating Lymphocyte Analysis Top

The clinical trials done all over the world in the last few decades have revealed that the quantity, subtype, and position/orientation of immune infiltrates in primary tumors are prognostic for disease-free survival and OS.[25] “Quantifying CD8+ TILs together with TILs expressing either CD3 or CD45RO serves as the basis of immunoscore.” Immunoscore as a component of cancer classification has been proposed initially in colorectal cancer (CRC), breast cancer, or melanoma.[26] Quantitative pathology based on the quantification of CD3+ and CD8+ TILs in the tumor core and the invasive margin has been advocated to develop a standardized algorithm to determine antitumor immune responses. Hence, international validation and acceptance of immunophenotyping of tumors may lead to introduction and implementation of the immunoscore as a new factor for the cancer classification, labeled as TNM-I (TNM-immune). It would better categorize cancer patients at baseline, would have a definite prognostic and predictive significance.[27]

The tool has been validated in breast cancer and CRC and could have a promising role in head-and-neck cancer too. Till date, in HNSCC, a programmed “immunoscore” evaluation on entire cross-sections has not been applied.[28] The literature review reveals inconsistency in assessment approach and threshold values as there is no standardized approach or cutoff value for evaluating TIL levels, thus making their role in HNSCC uncertain.[29] It has been postulated that the immune system may be particularly important in chemotherapy and radiation approaches as preexisting immunologic response has been associated with enhanced effects of these treatment modalities.[30] A high is in HNSCC is associated with lower levels of regulatory T-cells (Tregs), increased PD-L1 and MHC type I expressions in tumor cells, signifying its ability to identify anti-PD-1/PD-L1 therapy sensitive subset of tumors.

  TIL Evaluation in Head-and-Neck Squamous Cell Carcinoma Top

TIL subsets can guide disease progression into different directions based on an “agonist or antagonist” relation. Standardized assessment approaches are needed to evaluate TILs in tumor sections.[31] Based on the evaluation methods used in solid tumors (e.g., breast cancer, CRC, etc.), TILs have been categorized into two groups: stromal lymphocytes and intratumoral lymphocytes.[32] It has been observed that the distribution of T-cells also varies between tumor types; and within the same tumor type, some study groups show that varied subsets of T-cells are present in the core, stroma, and the invasive front. Histopathology-based studies which employ conventional H and E staining and immunohistochemistry (IHC) supported by a variety of descriptive, semiquantitative, and quantitative scoring methods have been used to evaluate TILs in tissue sections [Table 1].[33] However, these approaches have certain limitations such as subjective inter-and intraobserver variability and lack of diagnostic reproducibility which are addressed by automated image analysis methods, which focus on certain spatial or morphological aspects of the TME.[39] Digitization of histology slides has revolutionized the field and has ignited the development of methods for the automated digitized whole slide image analysis of tissue sections.[41] The image analysis softwares can identify stained immune cells and estimate their densities (n cells/mm2) in tissue sections and quantify them. The research studies have substantiated the high accuracy of automated systems over the optical counts.[33] The literature on TILs evaluation in oral cancer is still inconspicuous because of smaller sample sizes, heterogenous tissue sites, and lack of subsite-specific prognostic data.[42] Moreover, the lack of standardization of the different evaluation criteria used to make the results of different studies incomparable. The immune cell infiltration was analyzed in various tumor compartments, e.g., the invasive front, the tumor periphery, or the tumor nests, however, the exact definition and demarcation of these compartments is also unclear. If we compare the research work done over the past few decades, tissue samples obtained have been very inconsistent and nonuniform. Based on the preference or availability, resection samples, tissue microarrays, or incisional biopsy samples (may not be representative of the whole tumor) have been used. Furthermore, initial interpretation on a biopsy specimen may be confounded by the dynamics of pre/posttreatment, prognostic significance of which needs to be evaluated further. In OSCC, most of the immune biomarkers have been retrospectively studied, using archival tumor samples and thus may not reflect the impact of spatial and temporal intratumoral heterogeneity.[43] Due to these issues, a standardized, powerful immune stratification system, the immunoscore, needs to be delineated for OSCC along with standard cutoff values, based on the immune contexture to speed up the process of quantification thus facilitating routine diagnostic pathology.[24]
Table 1: Literature review

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  Potential Challenges Ahead Top

To establish the precision medicine-informed immunotherapy, there are few challenges that need to be addressed and some concepts that further need clarification. Most of the currently used methods of TIL quantification are subjective usually vary among different research groups and institutions, and therefore, it is necessary to develop standardized protocols for TILs quantification.[41] As advancement of digital analysis, quantitative IHC and quantitative multiplex immunofluorescence can be used for the scoring practice. Further analytical studies of TILs in patients undergoing standardized treatment regimens will be needed to determine how changes in infiltrates might mediate clinical benefit in patients with OSCC.[44] The current immunoscore scheme has not yet considered fully the role of cancer cell factors that modulate tumor immunogenicity [Figure 1]. The role of cancer cell-autonomous interferon gamma signaling in triggering an “inflamed” microenvironment has been recognized in several types of solid tumors, but still ambiguous in HNSCC. It would be essential to determine which complex set of genes are associated with a positive cytotoxic T-cell response.[45] Furthermore, separately evaluating potential biomarkers sans other factors could miscalculate the complexity of immune response. A dynamic communication between the immune system and the TME is facilitated by the complex oral and intestinal microbiota, ultimately modulating the efficacy of cancer therapies. Future research should consider the emerging immunomodulatory effects of the microbiota, as a predictive immune biomarker in OSCC.[9]

  Future Perspectives Top

Adoptive T-cell therapies, immune checkpoint inhibitors, costimulatory agonists, therapeutic vaccines, and monoclonal antibodies (mAbs) are currently studied immunotherapies. An important therapeutic backbone in various solid malignancies already includes anti-PD-1 agents which also have become the standard of care for the platinum-refractory R/M HNSCC.[46] In spite of immunomodulatory agents showing wonders in cancer, the response in patients is sometimes ephemeral. The reasons for therapeutic failure need to be investigated, and biomarkers to identify subsets of patients who are likely to respond should be explored along with the additional aspects of the immune response to cancer.[32] The antitumor immunity in HNSCC is depressed because of multiple factors including altered expression of immune checkpoint molecules and subsequently increased proportion of immunosuppressive Tregs in the TME and many other potential factors.[47] The need of hour is to study the mechanisms that inhibit or impede the development of OSCC by restoring immune homeostasis at the precancerous stage.[48]

  Conclusion Top

Detection of major cancer cell mechanisms that impede a favorable “inflamed” TME holds key to expand the patient pool who responds to novel adjuvant immunotherapy. Successful treatment plan centers on the improvement of TIL trafficking and activation synergizing with a checkpoint blockade-based regimen. High-throughput molecular profiling of the TME has enabled to understand the heterogeneity of the TME ultimately opening up new therapeutic options and can lead to resistant tumor formation through the process of immunoediting. IT agents have brought altogether new approach to treat cancer patients after treatment with multiple other modalities has been exhausted. The future of IT will rest on standardization and increased clinical utility of immune markers and evaluation of these agents in early-stage disease.

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Conflicts of interest

There are no conflicts of interest.

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