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BMC Cancer

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Open Access 01-12-2020 | Research article

The presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different subsets serve as prognostic factors in advanced hypopharyngeal squamous cell carcinoma

Authors: Jie Wang, Shu Tian, Ji Sun, Jiahao Zhang, Lan Lin, Chunyan Hu

Published in: BMC Cancer | Issue 1/2020

Abstract

Background

Cancer cells induce the infiltration of various immune cells that are located or distributed in different sites and play multiple roles, which have recently been proposed to predict clinical outcomes. We therefore studied the prognostic significance of the presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different types of immune cells in hypopharyngeal squamous cell carcinoma (HPSCC).

Methods

We retrospectively analysed 132 consecutive patients diagnosed with advanced HPSCC in 2013–2017. Tumoural parenchyma was immunohistochemically counted manually for the number of CD8, CD4 and Foxp3 cells. The ratios of CD8/Foxp3 and CD8/CD4 ratios were calculated for each specimen and analyzed with respect to patient clinicopathological variables and prognosis.

Results

HPSCC patients with high levels of TILs showed evident correlations with well differentiated tumors (P < 0.05). Moreover, Foxp3+ TIL is also associated with overall staging group and T category (P = 0.048 and P = 0.046, respectively). Kaplan-Meier analysis showed that high CD8 and FoxP3 infiltration correlated with favourable overall survival (OS, P = 0.019 and P = 0.001), disease-free survival (DFS, P = 0.045 and P = 0.028) and distant metastasis-free survival (DMFS, P = 0.034 and P = 0.009), respectively, but only Foxp3 displayed prognostic significance for DMFS in multivariate analysis (MVA). In the lymphocyte ratio analysis, CD8/Foxp3 appeared to play a pivotal role, and patients with a high CD8/Foxp3 ratio had a superior 3-year DFS and DMFS compared with those a low CD8/Foxp3 ratio in both univariate analysis (UVA) and MVA (P = 0.015 and P = 0.011). A high CD8/CD4 ratio was associated with better DFS and local relapse-free survival (LRFS) in UVA, and was an independent prognostic factor for improved LRFS in MVA (P = 0.040).

Conclusion

Although high TILs levels were determined to be prognostically significant in advanced HPSCC, the ratios of these subsets may be more informative. Particularly, a higher ratio of CD8/Foxp3 accurately predicts prognosis for improved DFS and DMFS, and an increased CD8/CD4 ratio is an independent predictor for favourable LRFS.

Weller P, Bankfalvi A, Gu X, Dominas N, Lehnerdt GF, Zeidler R, Lang S, Brandau S, Dumitru CA. The role of tumour FoxP3 as prognostic marker in different subtypes of head and neck cancer. Eur J Cancer. 2014;50(7):1291–300.PubMed

Ono T, Azuma K, Kawahara A, Akiba J, Kakuma T, Chitose S, Umeno H. Pre-treatment CD8(+) tumour-infiltrating lymphocyte density predicts distant metastasis after definitive treatment in patients with stage III/IV hypopharyngeal squamous cell carcinoma. Clinical Otolaryngol. 2018;43(5):1312–20.

Petersen JF, Timmermans AJ, van Dijk BAC, Overbeek LIH, Smit LA, Hilgers FJM, Stuiver MM, van den Brekel MWM. Trends in treatment, incidence and survival of hypopharynx cancer: a 20-year population-based study in the Netherlands. Eur Arch Otorhinolaryngol. 2018;275(1):181–9.PubMed

Newman JR, Connolly TM, Illing EA, Kilgore ML, Locher JL, Carroll WR. Survival trends in hypopharyngeal cancer: a population-based review. Laryngoscope. 2015;125(3):624–9.PubMed

Saifi M, Maran A, Raynaud P, Picot MC, Quittet P, Cartron G, Rossi JF, Costes V. High ratio of interfollicular CD8/FOXP3-positive regulatory T cells is associated with a high FLIPI index and poor overall survival in follicular lymphoma. Exp Ther Med. 2010;1(6):933–8.PubMedPubMedCentral

Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233(4770):1318–21.PubMed

Giatromanolaki A, Banham AH, Harris AL, Koukourakis MI. FOXP3 infiltrating lymphocyte density and PD-L1 expression in operable non-small cell lung carcinoma. Exp Lung Res. 2019;45(3–4):76–83.PubMed

Ou D, Adam J, Garberis I, Blanchard P, Nguyen F, Levy A, Casiraghi O, Gorphe P, Breuskin I, Janot F, et al. Clinical relevance of tumor 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):e1341030.PubMedPubMedCentral

Luen SJ, Savas P, Fox SB, Salgado R, Loi S. Tumour-infiltrating lymphocytes and the emerging role of immunotherapy in breast cancer. Pathology. 2017;49(2):141–55.PubMed

10.

Rojas IG, Spencer ML, Zapata PA, Martinez A, Alarcon R, Marchesani FJ, Tezal M. CD8+ and FoxP3+ T-cell infiltration in actinic cheilitis. Int J Dermatol. 2017;56(1):54–62.PubMed

11.

Harimoto H, Shimizu M, Nakagawa Y, Nakatsuka K, Wakabayashi A, Sakamoto C, Takahashi H. Inactivation of tumor-specific CD8(+) CTLs by tumor-infiltrating tolerogenic dendritic cells. Immunol Cell Biol. 2013;91(9):545–55.PubMedPubMedCentral

12.

Viguier M, Lemaitre F, Verola O, Cho MS, Gorochov G, Dubertret L, Bachelez H, Kourilsky P, Ferradini L. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol. 2004;173(2):1444–53.PubMed

13.

Jackute J, Zemaitis M, Pranys D, Sitkauskiene B, Miliauskas S, Bajoriunas V, Lavinskiene S, Sakalauskas R. The prognostic influence of tumor infiltrating Foxp3(+)CD4(+), CD4(+) and CD8(+) T cells in resected non-small cell lung cancer. J Inflamm. 2015;12:63.

14.

Quan H, Yan L, Wang S, Wang S. Clinical relevance and significance of programmed death-ligand 1 expression, tumor-infiltrating lymphocytes, and p16 status in sinonasal squamous cell carcinoma. Cancer Manag Res. 2019;11:4335–45.PubMedPubMedCentral

15.

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(3):354–63.PubMed

16.

Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Lee AH, Ellis IO, Green AR. An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Res Treat. 2011;127(1):99–108.PubMed

17.

Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.PubMed

18.

Kim HI, Kim H, Cho HW, Kim SY, Song KJ, Hyung WJ, Park CG, Kim CB. The ratio of intra-tumoral regulatory T cells (Foxp3+)/helper T cells (CD4+) is a prognostic factor and associated with recurrence pattern in gastric cardia cancer. J Surg Oncol. 2011;104(7):728–33.PubMed

19.

Asano Y, Kashiwagi S, Goto W, Kurata K, Noda S, Takashima T, Onoda N, Tanaka S, Ohsawa M, Hirakawa K. Tumour-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer. Br J Surg. 2016;103(7):845–54.PubMed

20.

Uryvaev A, Passhak M, Hershkovits D, Sabo E, Bar-Sela G. The role of tumor-infiltrating lymphocytes (TILs) as a predictive biomarker of response to anti-PD1 therapy in patients with metastatic non-small cell lung cancer or metastatic melanoma. Med Oncol. 2018;35(3):25.PubMed

21.

Semeraro M, Adam J, Stoll G, Louvet E, Chaba K, Poirier-Colame V, Sauvat A, Senovilla L, Vacchelli E, Bloy N, et al. The ratio of CD8(+)/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ. Oncoimmunology. 2016;5(10):e1218106.PubMedPubMedCentral

22.

Sideras K, Galjart B, Vasaturo A, Pedroza-Gonzalez A, Biermann K, Mancham S, Nigg AL, Hansen BE, Stoop HA, Zhou G, et al. Prognostic value of intra-tumoral CD8(+) /FoxP3(+) lymphocyte ratio in patients with resected colorectal cancer liver metastasis. J Surg Oncol. 2018;118(1):68–76.PubMedPubMedCentral

23.

Hu C, Tian S, Lin L, Zhang J, Ding H. Prognostic and clinicopathological significance of PD-L1 and tumor infiltrating lymphocytes in hypopharyngeal squamous cell carcinoma. Oral Oncol. 2020;102:104560.PubMed

24.

Mao Y, Qu Q, Chen X, Huang O, Wu J, Shen K. The prognostic value of tumor-infiltrating lymphocytes in breast Cancer: a systematic review and meta-analysis. PLoS One. 2016;11(4):e0152500.PubMedPubMedCentral

25.

Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol. 2012;124(2):192–8.PubMed

26.

Fang J, Li X, Ma D, Liu X, Chen Y, Wang Y, Lui VWY, Xia J, Cheng B, Wang Z. Prognostic significance of tumor infiltrating immune cells in oral squamous cell carcinoma. BMC Cancer. 2017;17(1):375.PubMedPubMedCentral

27.

Geng Y, Shao Y, He W, Hu W, Xu Y, Chen J, Wu C, Jiang J. Prognostic role of tumor-infiltrating lymphocytes in lung Cancer: a meta-analysis. Cellular Physiol Biochem. 2015;37(4):1560–71.

28.

Ni YH, Zhang XX, Lu ZY, Huang XF, Wang ZY, Yang Y, Dong YC, Jing Y, Song Y, Hou YY, et al. Tumor-Infiltrating CD1a(+) DCs and CD8(+)/FoxP3(+) Ratios Served as Predictors for Clinical Outcomes in Tongue Squamous Cell Carcinoma Patients. Pathol Oncol Res. 2020;26(3):1687–95.

29.

Machado I, Lopez-Guerrero JA, Scotlandi K, Picci P, Llombart-Bosch A. Immunohistochemical analysis and prognostic significance of PD-L1, PD-1, and CD8+ tumor-infiltrating lymphocytes in Ewing's sarcoma family of tumors (ESFT). Virchows Archiv. 2018;472(5):815–24.PubMed

30.

Wakabayashi O, Yamazaki K, Oizumi S, Hommura F, Kinoshita I, Ogura S, Dosaka-Akita H, Nishimura M. CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Sci. 2003;94(11):1003–9.PubMed

31.

Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.PubMed

32.

Watanabe Y, Katou F, Ohtani H, Nakayama T, Yoshie O, Hashimoto K. Tumor-infiltrating lymphocytes, particularly the balance between CD8(+) T cells and CCR4(+) regulatory T cells, affect the survival of patients with oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;109(5):744–52.PubMed

33.

Peng GL, Li L, Guo YW, Yu P, Yin XJ, Wang S, Liu CP. CD8(+) cytotoxic and FoxP3(+) regulatory T lymphocytes serve as prognostic factors in breast cancer. Am J Transl Res. 2019;11(8):5039–53.PubMedPubMedCentral

34.

Balermpas P, Michel Y, Wagenblast J, Seitz O, Weiss C, Rodel F, Rodel C, Fokas E. Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer. Br J Cancer. 2014;110(2):501–9.PubMed

35.

Ohtani H. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun. 2007;7:4.PubMedPubMedCentral

36.

Schumacher K, Haensch W, Roefzaad C, Schlag PM. Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res. 2001;61(10):3932–6.PubMed

37.

Fritzsching B, Fellenberg J, Moskovszky L, Sapi Z, Krenacs T, Machado I, Poeschl J, Lehner B, Szendroi M, Bosch AL, et al. CD8(+)/FOXP3(+)-ratio in osteosarcoma microenvironment separates survivors from non-survivors: a multicenter validated retrospective study. Oncoimmunology. 2015;4(3):e990800.PubMedPubMedCentral

38.

Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, Sozaki M, Tanaka M, Onishi H, Morisaki T, et al. Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. Cancer Immunol Immunother. 2010;59(5):653–61.PubMed

39.

Miyashita M, Sasano H, Tamaki K, Hirakawa H, Takahashi Y, Nakagawa S, Watanabe G, Tada H, Suzuki A, Ohuchi N, et al. Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study. Breast Cancer Res. 2015;17:124.PubMedPubMedCentral

40.

Nasman A, Romanitan M, Nordfors C, Grun N, Johansson H, Hammarstedt L, Marklund L, Munck-Wikland E, Dalianis T, Ramqvist T. Tumor infiltrating CD8+ and Foxp3+ lymphocytes correlate to clinical outcome and human papillomavirus (HPV) status in tonsillar cancer. PLoS One. 2012;7(6):e38711.PubMedPubMedCentral

41.

Li J, Wang J, Chen R, Bai Y, Lu X. The prognostic value of tumor-infiltrating T lymphocytes in ovarian cancer. Oncotarget. 2017;8(9):15621–31.PubMedPubMedCentral

42.

Boxberg M, Leising L, Steiger K, Jesinghaus M, Alkhamas A, Mielke M, Pfarr N, Gotz C, Wolff KD, Weichert W, et al. Composition and clinical impact of the immunologic tumor microenvironment in Oral squamous cell carcinoma. J Immunol. 2019;202(1):278–91.PubMed

43.

dos antos Pereira J, da Costa Miguel MC, Guedes Queiroz LM, da Silveira EJ. Analysis of CD8+ and CD4+ cells in oral squamous cell carcinoma and their association with lymph node metastasis and histologic grade of malignancy. Appl Immunohistochem Mol Morphol. 2014;22(3):200–5.

44.

Huang Z, Su W, Han Z, Yin J, Zhang Y, Li X. Tumor metastasis in patients with non-small cell lung cancer is inversely correlated with the number of tumor-infiltrating CD8(+) T cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2019;35(3):266–70.PubMed

45.

Kimura H, Matsui Y, Ishikawa A, Nakajima T, Iizasa T. Randomized controlled phase III trial of adjuvant chemoimmunotherapy with activated cytotoxic T cells and dendritic cells from regional lymph nodes of patients with lung cancer. Cancer Immunol Immunother. 2018;67(8):1231–8.PubMedPubMedCentral

46.

Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102(51):18538–43.PubMedPubMedCentral

47.

Diederichsen AC, Hjelmborg J, Christensen PB, Zeuthen J, Fenger C. Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol Immunother. 2003;52(7):423–8.PubMed

48.

Piersma SJ, Jordanova ES, van Poelgeest MI, Kwappenberg KM, van der Hulst JM, Drijfhout JW, Melief CJ, Kenter GG, Fleuren GJ, Offringa R, et al. High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Res. 2007;67(1):354–61.PubMed

49.

Krupar R, Hautmann MG, Pathak RR, Varier I, McLaren C, Gaag D, Hellerbrand C, Evert M, Laban S, Idel C, et al. Immunometabolic determinants of Chemoradiotherapy response and survival in head and neck squamous cell carcinoma. Am J Pathol. 2018;188(1):72–83.PubMed

50.

Wolf GT, Chepeha DB, Bellile E, Nguyen A, Thomas D, McHugh J, University of Michigan H, Neck SP. Tumor infiltrating lymphocytes (TIL) and prognosis in oral cavity squamous carcinoma: a preliminary study. Oral Oncol. 2015;51(1):90–5.PubMed

Title: The presence of tumour-infiltrating lymphocytes (TILs) and the ratios between different subsets serve as prognostic factors in advanced hypopharyngeal squamous cell carcinoma
Authors: Jie Wang
Shu Tian
Ji Sun
Jiahao Zhang
Lan Lin
Chunyan Hu
Publication date: 01-12-2020
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2020
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-020-07234-0

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