|Year : 2022 | Volume
| Issue : 2 | Page : 73-79
Unraveling the significance of immune contexture in oral cancer
Deepti Sharma1, George Koshy1, Vishal Kumar Sharma2, Gauri Malik3
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 Submission||21-Apr-2021|
|Date of Acceptance||29-May-2020|
|Date of Web Publication||16-Nov-2022|
Department of Oral Pathology and Microbiology, Christian Dental College and Hospital, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
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. 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. 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. 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. 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.
| Cancer Immunological Concept|| |
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. 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. 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. “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.
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. 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). 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.
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., TILs also have been translated into a therapeutic agent in adoptive cell transfer-based treatments of cancer, mostly of solid malignancies. 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.
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.” 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. In HNSCC, the need for enhanced treatment options is acknowledged because of poor survival rates and significant toxicities resulted by existing treatment strategies. Therefore, elaborate knowledge of dynamic interaction between immune contexture and TME is critical for both selection of and reaction to treatment. 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.
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. 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. 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. 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.
| Immunoscore: Assessment Tool for Tumor-Infiltrating Lymphocyte Analysis|| |
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. “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. 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.
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. 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. 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. 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|| |
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. 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. 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]. 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. 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. 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. 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. 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. 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.
| Potential Challenges Ahead|| |
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. 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. 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. 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.
| Future Perspectives|| |
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. 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. 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. 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.
| Conclusion|| |
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.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424.
de Ruiter EJ, Ooft ML, Devriese LA, Willems SM The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis. Oncoimmunology 2017;6:1–10.
World Health Organization. Global Health Observatory. Geneva: World Health Organization; 2018. Available from: http:///who.int/gho/database/en/
. [Last accessed on 2019 Mar 26].
Feller L, Lemmer J Oral squamous cell carcinoma: Epidemiology, clinical presentation and treatment. J Cancer Ther 2012;3:263–8.
Matlung SE, Wilhelmina van Kempen PM, Bovenschen N, van Baarle D, Willems SM Differences in T-cell infiltrates and survival between HPV+ and HPV- oropharyngeal squamous cell carcinoma. Future Sci OA 2016;2:FSO88.
Peltanova B, Raudenska M, Masarik M Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: A systematic review. Mol Cancer 2019;18:63.
Balermpas P, Michel Y, Wagenblast J, Seitz O, Weiss C, Rödel F, et al
Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer. Br J Cancer 2014;110:501–9.
Liu Y, Guo J, Huang L Modulation of tumor microenvironment for immunotherapy: Focus on nanomaterial-based strategies. Theranostics 2020;10:3099–117.
Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 2017;14:717–34.
Oliva M, Spreafico A, Taberna M, Alemany L, Coburn B, Mesia R, et al
Immune biomarkers of response to immune-checkpoint inhibitors in head and neck squamous cell carcinoma. Ann Oncol 2019;30:57–67.
Russell S, Angell T, Lechner M, Liebertz D, Correa A, Sinha U, et al
Immune cell infiltration patterns and survival in head and neck squamous cell carcinoma. Head Neck Oncol 2013;5:24.
Balermpas P, Rödel F, Weiss C, Rödel C, Fokas E Tumour-infiltrating lymphocytes favor the response to chemoradiotherapy of head and neck cancer. Onco Immunol 2014;3:1–3.
De Meulenaere A, Vermassen T, Aspeslagh S, Vandecasteele K, Rottey S, Ferdinande L TILs in head and neck cancer: Ready for clinical implementation and why (not)? Head Neck Pathol 2017;11:354–63.
Verdegaal EM Adoptive cell therapy: A highly successful individualized therapy for melanoma with great potential for other malignancies. Curr Opin Immunol 2016;39:90–5.
Schnell A, Schmidl C, Herr W, Siska PJ The peripheral and intratumoral immune cell landscape in cancer patients: A proxy for tumor biology and a tool for outcome prediction. Biomedicines 2018;6.
Lee KH, Kim EY, Yun JS, Park YL, Do SI, Chae SW, et al
The prognostic and predictive value of tumor-infiltrating lymphocytes and hematologic parameters in patients with breast cancer. BMC Cancer 2018;18:938.
Alsahafi E, Begg K, Amelio I, Raulf N, Lucarelli P, Sauter T, et al
Clinical update on head and neck cancer: Molecular biology and ongoing challenges. Cell Death Dis 2019;10:540.
Economopoulou P, Perisanidis C, Giotakis EI, Psyrri A The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): Anti-tumor immunity and clinical applications. Ann Transl Med 2016;4:173.
Boxberg M, Leising L, Steiger K, Jesinghaus M, Alkhamas A, Mielke M, et al
Composition and clinical impact of the immunologic tumor microenvironment in oral squamous cell carcinoma. J Immunol 2019;202:278–91.
Wang HC, Chan LP, Cho SF Targeting the immune microenvironment in the treatment of head and neck squamous cell carcinoma. Front Oncol 2019;9:1084.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al
Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313:1960–4.
Nagtegaal ID, Quirke P, Schmoll HJ Has the new TNM classification for colorectal cancer improved care? Nat Rev Clin Oncol 2011;9:119–23.
Mlecnik B, Bindea G, Pagès F, Galon J Tumor immunosurveillance in human cancers. Cancer Metastasis Rev 2011;30:5–12.
Lei Y, Xie Y, Tan YS, Prince ME, Moyer JS, Nör J, et al
. Telltale tumor infiltrating lymphocytes (TIL) in oral, head and neck cancer. Oral Oncol 2016;61:159–65.
Galon J, Angell HK, Bedognetti D, Marincola FM The continuum of cancer immunosurveillance: Prognostic, predictive, and mechanistic signatures. Immunity 2013;39:11–26.
Angell H, Galon J From the immune contexture to the Immunoscore: The role of prognostic and predictive immune markers in cancer. Curr Opin Immunol 2013;25:261–7.
Galon J, Pagès F, Marincola FM, Angell HK, Thurin M, Lugli A, et al
Cancer classification using the immunoscore: A worldwide task force. J Transl Med 2012;10:205–14.
Lechner A, Schlöber H, Rothschild SI, Thelen M, Reuter S, Zentis P Characterization of tumour-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma. Oncotarget 2017;8:44418–33.
Xu Q, Wang C, Xiaohong Yuan X, Feng Z, Han Z Prognostic value of tumour-infiltrating lymphocytes for patients with head and neck squamous cell carcinoma. Translational Oncology 2017;10:0–16.
Nguyen N, Bellile E, Thomas D, McHugh J, Rozek L, Virani S, et al
Tumor infiltrating lymphocytes and survival in patients with head and neck squamous cell carcinoma. Head Neck 2016;38:1074–84.
Öhman J, Mowjood R, Larsson L, Kovacs A, Magnusson B, Kjeller G, et al
Presence of CD3-positive T-cells in oral premalignant leukoplakia indicates prevention of cancer transformation. Anticancer Res 2015;35:311–7.
Rajjoub S, Basha RS, Einhorn E, Cohen MC, Marvel DM, Sewell DA Prognostic significance of tumorinfiltrating lymphocytes in oropharyngeal cancer. ENT J 2007;8:506–11.
Hendry S, Salgado R, Gevaert T, Russell PA, John T, Thapa B, et al
Assessing tumor infiltrating lymphocytes in solid tumors: A practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group: Part 1: Assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ
, metastatic tumor deposits and areas for further research. Adv Anat Pathol 2017;24:235–51.
Pretscher D, Distel LV, Grabenbauer GG, Wittlinger M, Buettner M, Niedobitek G Distribution of immune cells in head and neck cancer: CD8+ T-cells and CD20+ B-cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma. BMC Cancer 2009;9:292.
Zancope E, Costa NL, Junqueira-Kipnis AP, Valadares MC, Silva TA, Leles CR, et al
Differential infiltration of CD8+and NK cells in lip and oral cavity squamous cell carcinoma. J Oral Pathol Med 2010;39:162–7.
Brahmbhatt B, Vora H, Shah B Infiltration of T cell subsets during oral carcinogenesis. Indian J Oral Sci 2016;7:28–41.
Ou D, Adam J, Garberis I, Blanchard P, Nguyen F, Levy A Clinical relevance of tumour infiltrating lymphocytes, PD-L1 expression and correlation with HPV/p16 in head and neck cancer treated with bio- or chemo-radiotherapy. Oncoimmunology 2017;6:1–11.
Fang J, Xiaoxu Li X, Ma D, Liu X, Chen Y, Wang Y, et al
???. BMC Cancer 2017;17:375–84.
Steele KE, Tan TH, Korn R, Dacosta K, Brown C, Kuziora M, et al
Measuring multiple parameters of CD8+ tumor-infiltrating lymphocytes in human cancers by image analysis. J Immunother Cancer 2018;6:20.
Chen WU, Wu CT, Wang CW, Lan KH, Liang HK, Huang BS, et al
Prognostic significance of tumour-infiltrating lymphocytes in patients with operable tongue cancer. Radiat Oncol 2018;13:157–65.
Shaban M, Khurram SA, Fraz MM, Alsubaie N, Masood I, Mushtaq S, et al
A novel digital score for abundance of tumour infiltrating lymphocytes predicts disease free survival in oral squamous cell carcinoma. Sci Rep 2019;9:13341.
Uppaluri R, Dunn GP, Lewis JS Jr. Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in head and neck cancers. Cancer Immun 2008;8:16–26.
Hadler-Olsen E, Wirsing AM Tissue-infiltrating immune cells as prognostic markers in oral squamous cell carcinoma: A systematic review and meta-analysis. Br J Cancer 2019;120:714–27.
Wolf GT, Chepeha DB, Bellile E, Nguyen A, Thomas D, McHugh J, et al
Tumor infiltrating lymphocytes (TIL) and prognosis in oral cavity squamous carcinoma: A preliminary study. Oral Oncol 2015;51:90–5.
Wolf GT, Hudson JL, Peterson KA, Miller HL, McClatchey KD Lymphocyte subpopulations infiltrating squamous carcinomas of the head and neck: Correlations with extent of tumor and prognosis. Otolaryngol Head Neck Surg 1986;95:142–52.
Moskovitz J, Moy J, Ferris RL Immunotherapy for head and neck squamous cell carcinoma. Curr Oncol Rep 2018;20:22.
Suresh T, Burtness B The emerging role of immunotherapy in head and neck squamous cell cancer. AJHO 2017;13:20–7.
Sun Y, Liu N, Guan X, Wu H, Sun Z, Zeng H Immunosuppression induced by chronic inflammation and the progression to oral squamous cell carcinoma. Mediators Inflamm 2016;2016:5715719.