Tumor Infiltrating Lymphocytes as Immunebiomarkers in Oral Cancer: An Update


  • Deepti Sharma Department of Oral and Maxillofacial Pathology, Christian Dental College & Hospital, Ludhiana, Punjab, India https://orcid.org/0000-0002-2829-7139
  • Abi M. Thomas Department of Pedodontics and Preventive Dentistry, Christian Dental College & Hospital, Ludhiana, Punjab, India
  • George Koshy Department of Oral and Maxillofacial Pathology, Christian Dental College & Hospital, Ludhiana, Punjab, India




Immunotherapy, Immune markers, Oral cancer, Precision Medicine, Prognosis, Tumor infiltrating lymphocytes


The high morbidity and mortality associated with oral cancer has necessitated the exploration of newer diagnostic and prognostic biomarkers. In recent decades, targeting immune landscape has emerged as a newer approach as aggressive tumor biology and therapy resistance are influenced by the interplay between tumor and immune cells. A reciprocal association between chronic inflammation and carcinogenesis is well established and tumor infiltrating lymphocytes (TILs) represent inflammatory milieu of tumor microenvironment (TME). The varied T-cell phenotypes in different stages of cancer influence the prognostic and predictive response of the patients. Along with the conventional treatment options, Immunotherapy has evolved as a suitable alterative for oral carcinoma patients especially with recurrent and metastatic disease (R/M) but response is still unpredictable. Tumor microenvironment (TME) plays a key role to either lessen or boost up immune responses. There is an urgent need for extensive studies to be undertaken to better understand how tumor cells escape immune surveillance and resist immune attack. This review is an attempt to elucidate the concept of immune infiltrate in oral squamous cell carcinoma (OSCC) and thus, understanding the role of immunoscore as an adjunct to TNM staging to guide patient treatment.


Bray F, Ferlay J, Soerjomataram I, Siegel RL, Lindsey A, 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. https://doi.org/10.3322/caac.21492 DOI: https://doi.org/10.3322/caac.21492

World Health Organization. Global Health Observatory. Geneva: World Health Organization; 2018. who.int/gho/database/en/. May 26, 2023.

Feller L, Lemmer J. Oral squamous cell carcinoma: epidemiology, clinical presentation and treatment. J Cancer Ther 2012; 3(1): 263-68. https://doi.org/10.4236/jct.2012.34037 DOI: https://doi.org/10.4236/jct.2012.34037

Matlung SE, van Kempen PMW, Bovenschen N, D van Baarle, Willems SM. Differences in T-cell infiltrates and survival between HPV+ and HPV- oropharyngeal squamous cell carcinoma. Future Sci OA 2016; 2(1): 1-10. https://doi.org/10.4155/fso.15.88 DOI: https://doi.org/10.4155/fso.15.88

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(1): 63-87. https://doi.org/10.1186/s12943-019-0983-5 DOI: https://doi.org/10.1186/s12943-019-0983-5

Balermpas P, Michel Y, Wagenblast J, Seitz O, Weiss C, Rodel F et al. Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer. Br J Cancer 2014; 110(2): 501-9. https://doi.org/10.1038/bjc.2013.640 DOI: https://doi.org/10.1038/bjc.2013.640

Liu Y, Guo J, Huang L. Modulation of tumor micro-environment for immunotherapy: focus on nanomaterial-based strategies. Theranostics 2020; 10(7): 3099-3117. https://doi.org/10.7150/thno.42998 DOI: https://doi.org/10.7150/thno.42998

Bruni D, Angell HK, Galon J. The immune contexture and immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer 2020; 20: 662-80. https://doi.org/10.1038/s41568-020-0285-7 DOI: https://doi.org/10.1038/s41568-020-0285-7

Meulenaere AD, Vermassen T, Aspeslagh S Vandecasteele K, Rottey S, Ferdinande L. TILs in Head and Neck Cancer: Ready for Clinical Implementation and Why (Not)? Head and Neck Pathol 2017; 11: 354-363. https://doi.org/10.1007/s12105-016-0776-8 DOI: https://doi.org/10.1007/s12105-016-0776-8

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. https://doi.org/10.4161/onci.27403 DOI: https://doi.org/10.4161/onci.27403

Rajjoub S, Basha RS, Einhorn E, Cohen MC, Marvel DM, Sewell DA. Prognostic significance of tumorinfiltrating lymphocytes in oropharyngeal cancer. ENT-Journal 2007; 8(8): 506-11. https://doi.org/10.1177/014556130708600819 DOI: https://doi.org/10.1177/014556130708600819

Verdegaal EME. Adoptive cell therapy: a highly successful individualized therapy for melanoma with great potential for other malignancies. Curr Opin Immunol.2016; 39: 90-95. https://doi.org/10.1016/j.coi.2016.01.004 DOI: https://doi.org/10.1016/j.coi.2016.01.004

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 tumours predict clinical outcome. Science 2006; 313: 1960-4. https://doi.org/10.1126/science.1129139 DOI: https://doi.org/10.1126/science.1129139

Nagtegaal ID, Quirke P, Schmoll HJ. Has the new TNM classification for colorectal cancer improved care? Nat Rev Clin Oncol 2011; 9: 119-123. https://doi.org/10.1038/nrclinonc.2011.157 DOI: https://doi.org/10.1038/nrclinonc.2011.157

Mlecnik B, Bindea G, Pages F, Galon J. Tumor immunosurveillance in human cancers. Cancer Metastasis Rev 2011; 30: 5-12. https://doi.org/10.1007/s10555-011-9270-7 DOI: https://doi.org/10.1007/s10555-011-9270-7

Moskovitz J, Moy J, Ferris RL. Immunotherapy for Head and Neck Squamous Cell Carcinoma. Curr Oncol Rep 2018; 20: 22-9. https://doi.org/10.1007/s11912-018-0654-5 DOI: https://doi.org/10.1007/s11912-018-0654-5

SureshBabu SK, Godbole JH, Vaibhaw A, Chiplunkar SV. Immunosuppressive microenvironment in oral cancer: implications for cancer immunotherapy. Explor Immunol 2021; 1: 166-98. https://doi.org/10.37349/ei.2021.00013 DOI: https://doi.org/10.37349/ei.2021.00013

Gong J, Chehrazi-Raffle A, Reddi S, Salgia. Development of PD-1 and PD-L1 Inhibitors as a Form of Cancer Immunotherapy: a Comprehensive Review of Registration Trials and Future Considerations. J Immunother Cancer 2018; 6: 8-26. https://doi.org/10.1186/s40425-018-0316-z DOI: https://doi.org/10.1186/s40425-018-0316-z

Yi M, Jiao D, Xu H, Liu Q, Zhao W, Han X et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Molecular Cancer 2018; 17(1): 129. https://doi.org/10.1186/s12943-018-0864-3 DOI: https://doi.org/10.1186/s12943-018-0864-3

Ma W, Pham B, Li T. Cancer neoantigens as potential targets for immunotherapy. Clin Exp Metastasis 2022; 39(1): 51-60. https://doi.org/10.1007/s10585-021-10091-1 DOI: https://doi.org/10.1007/s10585-021-10091-1

Wang HC, Chan LP, Cho SF. Targeting the Immune Microenvironment in the Treatment of Head and Neck Squamous Cell Carcinoma. Front Oncol 2019; 9: 1084-95. https://doi.org/10.3389/fonc.2019.01084 DOI: https://doi.org/10.3389/fonc.2019.01084

Dasgupta S, Chakrabarti S, Deb AR. Tumor infiltrating lymphocytes in head and neck squamous cell carcinoma - Evaluation and clinical impact. J Can Res Ther 2022; 18: 49-54. https://doi.org/10.4103/jcrt.JCRT_830_20 DOI: https://doi.org/10.4103/jcrt.JCRT_830_20

Hendry S, Salgado R, GevaertT, 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(5): 235-251. https://doi.org/10.1097/PAP.0000000000000162 DOI: https://doi.org/10.1097/PAP.0000000000000162

Almangush A, Jouhi L, Atula T, Haglund C, Mäkitie AA, Hagström J, et al. Tumour-infiltrating lymphocytes in oropharyngeal cancer: a validation study according to the criteria of the International Immuno-Oncology Biomarker Working Group. Br J Cancer 2022; 126: 1589-94. https://doi.org/10.1038/s41416-022-01708-7 DOI: https://doi.org/10.1038/s41416-022-01708-7

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 2: TILs in melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors. Adv Anat Pathol 2017; 24(6): 311-335. https://doi.org/10.1097/PAP.0000000000000161 DOI: https://doi.org/10.1097/PAP.0000000000000161

Steele KE, Tan TH, Korn R, Dacosta K, Brown C, Kuziora M, et al. Measuring multiple parameters of CD8+ tumour-infiltrating lymphocytes in human cancers by image analysis. J Immunother Cancer 2018; 6: 20: 1-14. https://doi.org/10.1186/s40425-018-0326-x DOI: https://doi.org/10.1186/s40425-018-0326-x

Shaban M, Khurram S, Fraz MM, Alsubaie N, Iqra, Masood I, et al. A Novel Digital Score for Abundance of TumorInfiltrating Lymphocytes Predicts Disease Free Survival in Oral Squamous Cell Carcinoma. Scientific Reports 2019; 9: 13341. https://doi.org/10.1038/s41598-019-49710-z DOI: https://doi.org/10.1038/s41598-019-49710-z

Huang Y, Lin C, Kao HK,Hung SY, Ko HJ, Huang YC, et al. Digital Image Analysis of CD8+ and CD3+ Tumor-Infiltrating Lymphocytes in Tongue Squamous Cell Carcinoma. Cancer Management and Research 2020; 12: 8275-8285. https://doi.org/10.2147/CMAR.S255816 DOI: https://doi.org/10.2147/CMAR.S255816

Diao P, Jiang Y, Li Y, et al. Immune landscape and subtypes in primary resectable oral squamous cell carcinoma: prognostic significance and predictive of therapeutic response. J Immunother Cancer 2021; 9: e002434. https://doi.org/10.1136/jitc-2021-002434 DOI: https://doi.org/10.1136/jitc-2021-002434

Ou D, Adam J, GarberisI, 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(9): 1-11. https://doi.org/10.1080/2162402X.2017.1341030 DOI: https://doi.org/10.1080/2162402X.2017.1341030

Fang J, Li X, Ma D, Liu X, Chen Y, Wang Y, et al. Prognostic significance of tumor infiltrating immune cells in oral squamous cell carcinoma. BMC Cancer 2017; 17: 375-84. https://doi.org/10.1186/s12885-017-3317-2 DOI: https://doi.org/10.1186/s12885-017-3317-2

Lei Y, Xie Y, Tan YS, Prince ME, Moyer JS, Nör J, Wolf GT. Telltale Tumor Infiltrating Lymphocytes (TIL) in Oral, Head & Neck Cancer. Oral Oncol 2016; 61: 159-165. https://doi.org/10.1016/j.oraloncology.2016.08.003 DOI: https://doi.org/10.1016/j.oraloncology.2016.08.003

Hadler-Olsen E, Wirsing AM. Tissue-infiltrating immune cells as prognostic markers in oral squamous cell carcinoma: a systematic review and metaanalysis. Br J Can 2019 120: 714-727. https://doi.org/10.1038/s41416-019-0409-6 DOI: https://doi.org/10.1038/s41416-019-0409-6

Lee KH, Kim EU, Yun SJ, Park YL, Do SI, Chae SW, et al. The prognostic and predictive value of tumour-infiltrating lymphocytes and hematologic parameters in patients with breast cancer. BMC Cancer 2018; 18: 938-47. https://doi.org/10.1186/s12885-018-4832-5 DOI: https://doi.org/10.1186/s12885-018-4832-5

Boxberg M, Leising L, Steiger K, Jesinghaus M, Alkhamas A, Mielke M, et al. J Immunol 2019; 202: 278-291. https://doi.org/10.4049/jimmunol.1800242 DOI: https://doi.org/10.4049/jimmunol.1800242

Ohman 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: 311-318.

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(1): 0-16. https://doi.org/10.1016/j.tranon.2016.10.005 DOI: https://doi.org/10.1016/j.tranon.2016.10.005

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. https://doi.org/10.1186/1479-5876-10-205 DOI: https://doi.org/10.1186/1479-5876-10-1

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(7): 1074-84. https://doi.org/10.1002/hed.24406 DOI: https://doi.org/10.1002/hed.24406

Fridman WH, Zitvogel L, Saute`s-Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 2017; 14(12): 717-734. https://doi.org/10.1038/nrclinonc.2017.101 DOI: https://doi.org/10.1038/nrclinonc.2017.101

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. Mediat Inflamm 2016; 2016: 1-12. https://doi.org/10.1155/2016/5715719 DOI: https://doi.org/10.1155/2016/5715719

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(1): 90-95. https://doi.org/10.1016/j.oraloncology.2014.09.006 DOI: https://doi.org/10.1016/j.oraloncology.2014.09.006

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. Otolaryngology-Head and Neck Surgery 1986; 95: 142-52. https://doi.org/10.1177/019459988609500203 DOI: https://doi.org/10.1177/019459988609500203

Pignatelli P, Romei FM, Bondi D, Giuliani M, Piattelli A, Curia MC. Microbiota and Oral Cancer as A Complex and Dynamic Microenvironment: A Narrative Review from Etiology to Prognosis. Int J Mol Sci 2022; 23: 8323. https://doi.org/10.1177/019459988609500203 DOI: https://doi.org/10.3390/ijms23158323

Pretscher D, Distel LV, Grabenbauer GG, Wittlinger M, Buettner G, et al. 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: 292-302. https://doi.org/10.1186/1471-2407-9-292 DOI: https://doi.org/10.1186/1471-2407-9-292

Zancope E, Costa NL, Junqueira-Kipnis AP, Valadares MC, Silva TA, Leles CR. Differential infiltration of CD8+ and NK cells in lip and oral cavity squamous cell carcinoma. J Oral Pathol Med 2010; 39: 162-7. https://doi.org/10.1111/j.1600-0714.2009.00792.x DOI: https://doi.org/10.1111/j.1600-0714.2009.00792.x

Brahmbhatt B, Vora H, Shah B. Infiltration of T cell subsets during oral carcinogenesis. Indian J Oral Sci 2016; 7: 28-41. https://doi.org/10.4103/0976-6944.176384 DOI: https://doi.org/10.4103/0976-6944.176384

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. https://doi.org/10.1186/s13014-018-1099-6 DOI: https://doi.org/10.1186/s13014-018-1099-6

Caruntu C, Zurac S. Prognostic Potential of Tumor-Infiltrating Immune Cells in Resectable Oral Squamous Cell Carcinoma. Cancers 2021; 13: 2268. https://doi.org/10.3390/cancers13092268 DOI: https://doi.org/10.3390/cancers13092268




How to Cite

Sharma, D., Thomas, A. M., & Koshy, G. (2023). Tumor Infiltrating Lymphocytes as Immunebiomarkers in Oral Cancer: An Update. Journal of Cancer Research Updates, 12, 33–39. https://doi.org/10.30683/1929-2279.2023.12.6