. 2021 May; 9(5):.
doi: 10.3390/biomedicines9050486.

Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis

Juan P Rodrigo 1 Mario Sánchez-Canteli 1 Fernando López 1 Gregory T Wolf 2 Juan C Hernández-Prera 3 Michelle D Williams 4 Stefan M Willems 5 Alessandro Franchi 6 Andrés Coca-Pelaz 1 Alfio Ferlito 7 
  • PMID: 33925205
  •     49 References
  •     2 citations


The presence of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment has been demonstrated to be of prognostic value in various cancers. In this systematic review and meta-analysis, we investigated the prognostic value of TIL in laryngeal squamous cell carcinoma (LSCC). We performed a systematic search in PubMed for publications that investigated the prognostic value of TIL in LSCC. A meta-analysis was performed including all studies assessing the association between TIL counts in hematoxylin-eosin (HE)-stained sections, for CD8+ and/or CD3+/CD4+ TIL and overall survival (OS) or disease-free survival (DFS). The pooled meta-analysis showed a favorable prognostic role for stromal TIL in HE sections for OS (HR 0.57, 95% CI 0.36-0.91, p = 0.02), and for DFS (HR 0.56, 95% CI 0.34-0.94, p = 0.03). High CD8+ TIL were associated with a prolonged OS (HR 0.62, 95% CI 0.4-0.97, p = 0.04) and DFS (HR 0.73, 95% CI 0.34-0.94, p = 0.002). High CD3+/CD4+ TIL demonstrated improved OS (HR 0.32, 95% CI 0.16-0.9, p = 0.03) and DFS (HR 0.23, 95% CI 0.10-0.53, p = 0.0005). This meta-analysis confirmed the favorable prognostic significance of TIL in LSCC. High stromal TIL evaluated in HE sections and intra-tumoral and stromal CD3+, CD4+ and/or CD8+ TIL might predict a better clinical outcome.

Keywords: larynx; prognosis; squamous cell carcinoma; tumor-infiltrating lymphocytes.

Prognostic Impact of Tumor-Infiltrating Lymphocytes in Laryngeal Squamous Cell Carcinoma Patients.
Duo Zhang, Di Tang, +4 authors, Li-Ming Lu.
Laryngoscope, 2020 Oct 28; 131(4). PMID: 33107987
Postoperative radiotherapy for laryngeal cancer. The prognostic role of programmed death-ligand 1: An immune microenvironment-based cluster analysis.
Leonardo Franz, Lara Alessandrini, +5 authors, Gino Marioni.
Pathol Res Pract, 2020 Aug 23; 216(9). PMID: 32825972
Proportion of CD4 and CD8 tumor infiltrating lymphocytes predicts survival in persistent/recurrent laryngeal squamous cell carcinoma.
Rebecca Hoesli, Andrew C Birkeland, +12 authors, Matthew E Spector.
Oral Oncol, 2018 Jan 25; 77. PMID: 29362129    Free PMC article.
Head and neck squamous cell carcinoma.
Daniel E Johnson, Barbara Burtness, +3 authors, Jennifer R Grandis.
Nat Rev Dis Primers, 2020 Nov 28; 6(1). PMID: 33243986    Free PMC article.
Prognostic impact of neutrophils-to-lymphocytes ratio (NLR), PD-L1 expression, and tumor immune microenvironment in laryngeal cancer.
Leonardo Franz, Lara Alessandrini, +4 authors, Gino Marioni.
Ann Diagn Pathol, 2020 Nov 15; 50. PMID: 33189034
TILs in Head and Neck Cancer: Ready for Clinical Implementation and Why (Not)?
Astrid De Meulenaere, Tijl Vermassen, +3 authors, Liesbeth Ferdinande.
Head Neck Pathol, 2016 Dec 30; 11(3). PMID: 28032290    Free PMC article.
Prognostic Value of Tumor-Infiltrating Lymphocytes in Head and Neck Squamous Cell Carcinoma.
Matthew E Spector, Emily Bellile, +10 authors, University of Michigan Head and Neck SPORE Program.
JAMA Otolaryngol Head Neck Surg, 2019 Sep 06; 145(11). PMID: 31486841    Free PMC article.
The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis.
Emma J de Ruiter, Marc L Ooft, Lot A Devriese, Stefan M Willems.
Oncoimmunology, 2017 Nov 18; 6(11). PMID: 29147608    Free PMC article.
Highly Cited. Review.
The ratio of CD4/CD8 T-cells in human papillomavirus-positive laryngeal squamous cell carcinoma accounts for improved outcome.
Duo Zhang, Wei-Jing Tang, +4 authors, Li-Ming Lu.
Acta Otolaryngol, 2016 Apr 16; 136(8). PMID: 27080151
The Link between the Multiverse of Immune Microenvironments in Metastases and the Survival of Colorectal Cancer Patients.
Marc Van den Eynde, Bernhard Mlecnik, +23 authors, Jérôme Galon.
Cancer Cell, 2018 Dec 12; 34(6). PMID: 30537506
Highly Cited.
The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis.
M J M Gooden, G H de Bock, +2 authors, H W Nijman.
Br J Cancer, 2011 Jun 02; 105(1). PMID: 21629244    Free PMC article.
Highly Cited. Systematic Review.
Overall assessment of tumor-infiltrating lymphocytes in head and neck squamous cell carcinoma: time to take notice.
Alhadi Almangush, Ilmo Leivo, Antti A Mäkitie.
Acta Otolaryngol, 2020 Feb 06; 140(3). PMID: 32022615
International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.
Franck Pagès, Bernhard Mlecnik, +96 authors, Jérôme Galon.
Lancet, 2018 May 15; 391(10135). PMID: 29754777
Highly Cited.
Prognostic role of programmed death ligand 1 (PD-L1) and the immune microenvironment in laryngeal carcinoma.
Lara Alessandrini, Leonardo Franz, +4 authors, Gino Marioni.
Oral Oncol, 2020 Jun 09; 108. PMID: 32512470
Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.
Larissa Shamseer, David Moher, +6 authors, PRISMA-P Group.
BMJ, 2015 Jan 04; 350. PMID: 25555855
Highly Cited.
Immunology and Immunotherapy of Head and Neck Cancer.
Robert L Ferris.
J Clin Oncol, 2015 Sep 10; 33(29). PMID: 26351330    Free PMC article.
Highly Cited. Review.
Tumor infiltrating lymphocytes and survival in patients with head and neck squamous cell carcinoma.
Nghia Nguyen, Emily Bellile, +15 authors, Head and Neck SPORE Program Investigators.
Head Neck, 2016 Feb 18; 38(7). PMID: 26879675    Free PMC article.
Highly Cited.
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.
Shona Hendry, Roberto Salgado, +97 authors, Stephen B Fox.
Adv Anat Pathol, 2017 Aug 05; 24(6). PMID: 28777143    Free PMC article.
Highly Cited. Review.
Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology 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.
Shona Hendry, Roberto Salgado, +97 authors, Stephen B Fox.
Adv Anat Pathol, 2017 Aug 05; 24(5). PMID: 28777142    Free PMC article.
Highly Cited. Review.
Expression of PD-L1 on Immune Cells Shows Better Prognosis in Laryngeal, Oropharygeal, and Hypopharyngeal Cancer.
Ede Birtalan, Kornel Danos, +11 authors, Laszlo Tamas.
Appl Immunohistochem Mol Morphol, 2017 Dec 23; 26(7). PMID: 29271789
Tumour-infiltrating lymphocytes in the risk stratification of squamous cell carcinoma of the head and neck.
T M Jones.
Br J Cancer, 2014 Jan 23; 110(2). PMID: 24448392    Free PMC article.
Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers.
Cécile Badoual, Stéphane Hans, +9 authors, Eric Tartour.
Clin Cancer Res, 2006 Jan 24; 12(2). PMID: 16428488
Highly Cited.
Assessment of tumor-associated immune cells in laryngeal squamous cell carcinoma.
Liyuan Zhou, Yujun Li, +9 authors, Binquan Wang.
J Cancer Res Clin Oncol, 2019 May 23; 145(7). PMID: 31115672
A role for the immune system in advanced laryngeal cancer.
Marta Tagliabue, Fausto Maffini, +18 authors, Mohssen Ansarin.
Sci Rep, 2020 Oct 29; 10(1). PMID: 33110100    Free PMC article.
IL-23R in laryngeal cancer: a cancer immunoediting process that facilitates tumor cell proliferation and results in cisplatin resistance.
Ye Tao, Hailong Shen, +3 authors, Yehai Liu.
Carcinogenesis, 2020 Jun 12; 42(1). PMID: 32526010
Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer.
P Balermpas, Y Michel, +5 authors, E Fokas.
Br J Cancer, 2013 Oct 17; 110(2). PMID: 24129245    Free PMC article.
Highly Cited.
Evaluation of PD-L1 Expression and Associated Tumor-Infiltrating Lymphocytes in Laryngeal Squamous Cell Carcinoma.
Maria Vassilakopoulou, Margaritis Avgeris, +11 authors, Amanda Psyrri.
Clin Cancer Res, 2015 Sep 27; 22(3). PMID: 26408403
Highly Cited.
Analysis of tumor-infiltrating CD103 resident memory T-cell content in recurrent laryngeal squamous cell carcinoma.
Jacqueline E Mann, Joshua D Smith, +16 authors, J Chad Brenner.
Cancer Immunol Immunother, 2018 Oct 27; 68(2). PMID: 30361882    Free PMC article.
Towards the introduction of the 'Immunoscore' in the classification of malignant tumours.
Jérôme Galon, Bernhard Mlecnik, +45 authors, Franck Pagès.
J Pathol, 2013 Oct 15; 232(2). PMID: 24122236    Free PMC article.
Highly Cited. Review.
Predictive value of CD8/FOXP3 ratio combined with PD-L1 expression for radiosensitivity in patients with squamous cell carcinoma of the larynx receiving definitive radiation therapy.
Takeharu Ono, Koichi Azuma, +7 authors, Hirohito Umeno.
Head Neck, 2020 Aug 19; 42(12). PMID: 32808399
The Immunoscore: Colon Cancer and Beyond.
Helen K Angell, Daniela Bruni, +2 authors, Jérôme Galon.
Clin Cancer Res, 2019 Aug 16; 26(2). PMID: 31413009
Highly Cited. Review.
Prognostic impact of immune microenvironment in laryngeal and pharyngeal squamous cell carcinoma: Immune cell subtypes, immuno-suppressive pathways and clinicopathologic characteristics.
Georgia Karpathiou, Francois Casteillo, +7 authors, Michel Peoc'h.
Oncotarget, 2016 Dec 31; 8(12). PMID: 28038471    Free PMC article.
Characteristics and impact of programmed death-ligand 1 expression, CD8+ tumor-infiltrating lymphocytes, and p16 status in head and neck squamous cell carcinoma.
Nuttapong Ngamphaiboon, Teeranuch Chureemas, +6 authors, Noppadol Larbcharoensub.
Med Oncol, 2019 Jan 23; 36(2). PMID: 30666437
Functionally distinct subsets of CD4⁺ regulatory T cells in patients with laryngeal squamous cell carcinoma are indicative of immune deregulation and disease progression.
Wei Sun, Wei-Jin Li, +8 authors, Wei-Ping Wen.
Oncol Rep, 2014 Oct 22; 33(1). PMID: 25333227
Prognostic Significance of CD4+ and CD8+ Tumor-Infiltrating Lymphocytes in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis.
Daniele Borsetto, Michele Tomasoni, +8 authors, Paolo Boscolo-Rizzo.
Cancers (Basel), 2021 Mar 07; 13(4). PMID: 33668519    Free PMC article.
The immune score as a new possible approach for the classification of cancer.
Jérôme Galon, Franck Pagès, +5 authors, Paolo A Ascierto.
J Transl Med, 2012 Jan 05; 10. PMID: 22214470    Free PMC article.
Highly Cited.
Immunohistochemical analysis of lymphocytic infiltration in the tumor microenvironment in patients operated on for laryngeal cancer.
A Gabriel, G Namyslowski, +3 authors, P Urbaniec.
Eur Arch Otorhinolaryngol, 1999 Oct 20; 256(8). PMID: 10525939
Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma.
Douglas J Hartman, Fahad Ahmad, +2 authors, Liron Pantanowitz.
Oral Oncol, 2018 Nov 10; 86. PMID: 30409313    Free PMC article.
A high ratio of IL-12Rβ2-positive tumor-infiltrating lymphocytes indicates favorable prognosis in laryngeal cancer.
Ye Tao, Neil Gross, +4 authors, Jianming Yang.
Oral Oncol, 2017 Nov 07; 74. PMID: 29103744
Tumor Infiltrating Lymphocytes and CD8+ T Cell Subsets as Prognostic Markers in Patients with Surgically Treated Laryngeal Squamous Cell Carcinoma.
Kyriakos Chatzopoulos, Vassiliki Kotoula, +7 authors, Georgios Fountzilas.
Head Neck Pathol, 2019 Nov 22; 14(3). PMID: 31749124    Free PMC article.
Digital pathology-aided assessment of tumor-infiltrating T lymphocytes in advanced stage, HPV-negative head and neck tumors.
Emma J de Ruiter, Reinout H de Roest, +4 authors, Stefan M Willems.
Cancer Immunol Immunother, 2020 Jan 26; 69(4). PMID: 31980916    Free PMC article.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
Freddie Bray, Jacques Ferlay, +3 authors, Ahmedin Jemal.
CA Cancer J Clin, 2018 Sep 13; 68(6). PMID: 30207593
Highly Cited.
The prognostic value of systemic and local inflammation in patients with laryngeal squamous cell carcinoma.
Jie Wang, Shengzi Wang, +4 authors, Hao Ding.
Onco Targets Ther, 2016 Dec 07; 9. PMID: 27920556    Free PMC article.
PD-1/PD-L1 Axis, Rather Than High-Mobility Group Alarmins or CD8+ Tumor-Infiltrating Lymphocytes, Is Associated With Survival in Head and Neck Squamous Cell Carcinoma Patients Who Received Surgical Resection.
Fan Yang, Ziqing Zeng, +3 authors, Xiubao Ren.
Front Oncol, 2019 Jan 09; 8. PMID: 30619746    Free PMC article.
Immune cell infiltration in head and neck squamous cell carcinoma and patient outcome: a retrospective study.
Karolin Schneider, Etienne Marbaix, +4 authors, Vincent Grégoire.
Acta Oncol, 2018 Mar 02; 57(9). PMID: 29493423
Expression of Programmed Death-Ligand 1 in Laryngeal Carcinoma and its Effects on Immune Cell Subgroup Infiltration.
Dan Yu, Jinzhang Cheng, +3 authors, Chengbi Xu.
Pathol Oncol Res, 2018 Oct 27; 25(4). PMID: 30361911
PD-L1 expression correlates with tumor-infiltrating lymphocytes and better prognosis in patients with HPV-negative head and neck squamous cell carcinomas.
Mario Sanchez-Canteli, Rocio Granda-Díaz, +7 authors, Juan P Rodrigo.
Cancer Immunol Immunother, 2020 May 26; 69(10). PMID: 32448984
Prognostic and predictive values of immune infiltrate in patients with head and neck squamous cell carcinoma.
Xue-Mei Zhang, Ling-Jun Song, +8 authors, Wei-Wei Shen.
Hum Pathol, 2018 Jul 24; 82. PMID: 30036594
Morphological observations of immunobiology of laryngeal cancer. Evaluation of the defensive activity of immunocompetent cells present in tumour stroma.
O Sala, A Ferlito.
Acta Otolaryngol, 1976 Mar 01; 81(3-4). PMID: 1266621
Novel Insights into the Immunotherapy of Soft Tissue Sarcomas: Do We Need a Change of Perspective?
Andrej Ozaniak, Jiri Vachtenheim, +2 authors, Zuzana Strizova.
Biomedicines, 2021 Aug 28; 9(8). PMID: 34440139    Free PMC article.
MicroRNAs: Their Role in Metabolism, Tumor Microenvironment, and Therapeutic Implications in Head and Neck Squamous Cell Carcinoma.
Shine-Gwo Shiah, Sung-Tau Chou, Jang-Yang Chang.
Cancers (Basel), 2021 Nov 28; 13(22). PMID: 34830755    Free PMC article.