Identification of the Tumor Infiltrating Lymphocytes (TILs) Landscape in Pure Squamous Cell Carcinoma of the Bladder

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Aug 26

PMID 36010989

Authors

Lennert Eismann

Severin Rodler

Alexander Buchner

Gerald Bastian Schulz

Yannic Volz

Robert Bischoff

Benedikt Ebner

Thilo Westhofen

Jozefina Casuscelli

Raphaela Waidelich

Christian Stief

Boris Schlenker

Stephan Ledderose

Affiliations

Soon will be listed here.

Abstract

Background: Tumor infiltrating lymphocytes (TILs) are known as important prognostic biomarkers and build the fundament for immunotherapy. However, the presence of TILs and its impact on outcome in pure squamous cell carcinoma (SCC) of the bladder remains uncertain. Methods: Out of 1600 patients undergoing radical cystectomy, 61 patients revealed pure bladder SCC in the final histopathological specimen. Retrospectively, immunohistochemical staining was performed on a subset of TILs (CD3+, CD4+, CD8+, CD20+). Endpoints were overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS). The Kaplan−Meier method was used to evaluate survival outcomes. Results: Strong infiltration of CD3+ was found in 27 (44%); of CD4+ in 28 (46%); of CD8+ in 26 (43%); and of CD20+ in 27 tumors (44%). Improved OS was observed for strong CD3+ (p < 0.001); CD4+ (p = 0.045); CD8+ (p = 0.001); and CD20+ infiltration (p < 0.001). Increased rates of PFS were observed for CD3+ (p = 0.025) and CD20+ TILs (p = 0.002). In multivariate analyses, strong CD3+ (HR: 0.163, CI: 0.044−0.614) and strong CD8+ TILs (HR: 0.265, CI: 0.081−0.864) were revealed as predictors for OS and the strong infiltration of CD20+ cells (HR: 0.095, CI: 0.019−0.464) for PFS. Conclusions: These first results of TILs in bladder SCC revealed predictive values of CD3+, CD8+ and CD20+.

Citing Articles

Characteristics of auto-quantified tumor-infiltrating lymphocytes and the prognostic value in adenocarcinoma of the esophagogastric junction, gastric adenocarcinoma, and esophageal squamous cell carcinoma.

Dong H, Yao L, Fan J, Gao P, Yang X, Yuan Z Aging (Albany NY). 2024; 16(13):11027-11061.

PMID: 38975889 PMC: 11272125. DOI: 10.18632/aging.205999.

Characterisation of tumour-immune phenotypes and PD-L1 positivity in squamous bladder cancer.

Jung M, Rose M, Knuechel R, Loeffler C, Muti H, Kather J BMC Cancer. 2023; 23(1):113.

PMID: 36726072 PMC: 9890720. DOI: 10.1186/s12885-023-10576-0.

References

Wouters M, Nelson B . Prognostic Significance of Tumor-Infiltrating B Cells and Plasma Cells in Human Cancer. Clin Cancer Res. 2018; 24(24):6125-6135. DOI: 10.1158/1078-0432.CCR-18-1481. View

Sharma P, Shen Y, Wen S, Yamada S, Jungbluth A, Gnjatic S . CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci U S A. 2007; 104(10):3967-72. PMC: 1820692. DOI: 10.1073/pnas.0611618104. View

Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J . Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017; 18(3):312-322. DOI: 10.1016/S1470-2045(17)30065-7. View

Catacchio I, Silvestris N, Scarpi E, Schirosi L, Scattone A, Mangia A . Intratumoral, rather than stromal, CD8+ T cells could be a potential negative prognostic marker in invasive breast cancer patients. Transl Oncol. 2019; 12(3):585-595. PMC: 6350084. DOI: 10.1016/j.tranon.2018.12.005. View

Kassouf W, Spiess P, Siefker-Radtke A, Swanson D, Grossman H, Kamat A . Outcome and patterns of recurrence of nonbilharzial pure squamous cell carcinoma of the bladder: a contemporary review of The University of Texas M D Anderson Cancer Center experience. Cancer. 2007; 110(4):764-9. DOI: 10.1002/cncr.22853. View

Shi M, Meng X, Wu Q, Zhou X . High CD3D/CD4 ratio predicts better survival in muscle-invasive bladder cancer. Cancer Manag Res. 2019; 11:2987-2995. PMC: 6489580. DOI: 10.2147/CMAR.S191105. View

Krpina K, Babarovic E, Jonjic N . Correlation of tumor-infiltrating lymphocytes with bladder cancer recurrence in patients with solitary low-grade urothelial carcinoma. Virchows Arch. 2015; 467(4):443-8. DOI: 10.1007/s00428-015-1808-6. View

Sikic D, Weyerer V, Geppert C, Bertz S, Lange F, Taubert H . Utility of stromal tumor infiltrating lymphocyte scoring (sTILs) for risk stratification of patients with muscle-invasive urothelial bladder cancer after radical cystectomy. Urol Oncol. 2021; 40(2):63.e19-63.e26. DOI: 10.1016/j.urolonc.2021.07.025. View

Willis D, Kamat A . Nonurothelial bladder cancer and rare variant histologies. Hematol Oncol Clin North Am. 2015; 29(2):237-52, viii. DOI: 10.1016/j.hoc.2014.10.011. View

10.

Kluth L, Black P, Bochner B, Catto J, Lerner S, Stenzl A . Prognostic and Prediction Tools in Bladder Cancer: A Comprehensive Review of the Literature. Eur Urol. 2015; 68(2):238-53. DOI: 10.1016/j.eururo.2015.01.032. View

11.

Bruni D, Angell H, Galon J . The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer. 2020; 20(11):662-680. DOI: 10.1038/s41568-020-0285-7. View

12.

Sharma P, Allison J . The future of immune checkpoint therapy. Science. 2015; 348(6230):56-61. DOI: 10.1126/science.aaa8172. View

13.

Tay R, Richardson E, Toh H . Revisiting the role of CD4 T cells in cancer immunotherapy-new insights into old paradigms. Cancer Gene Ther. 2020; 28(1-2):5-17. PMC: 7886651. DOI: 10.1038/s41417-020-0183-x. View

14.

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G . The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2014; 26(2):259-71. PMC: 6267863. DOI: 10.1093/annonc/mdu450. View

15.

Orhan A, Vogelsang R, Andersen M, Madsen M, Holmich E, Raskov H . The prognostic value of tumour-infiltrating lymphocytes in pancreatic cancer: a systematic review and meta-analysis. Eur J Cancer. 2020; 132:71-84. DOI: 10.1016/j.ejca.2020.03.013. View

16.

Giraldo N, Peske J, Sautes-Fridman C, Fridman W . Integrating histopathology, immune biomarkers, and molecular subgroups in solid cancer: the next step in precision oncology. Virchows Arch. 2019; 474(4):463-474. DOI: 10.1007/s00428-018-02517-1. View

17.

Miyake M, Hori S, Owari T, Oda Y, Tatsumi Y, Nakai Y . Clinical Impact of Tumor-Infiltrating Lymphocytes and PD-L1-Positive Cells as Prognostic and Predictive Biomarkers in Urological Malignancies and Retroperitoneal Sarcoma. Cancers (Basel). 2020; 12(11). PMC: 7692684. DOI: 10.3390/cancers12113153. View

18.

Schulz G, Grimm T, Sers C, Riemer P, Elmasry M, Kirchner T . Prognostic value and association with epithelial-mesenchymal transition and molecular subtypes of the proteoglycan biglycan in advanced bladder cancer. Urol Oncol. 2019; 37(8):530.e9-530.e18. DOI: 10.1016/j.urolonc.2019.05.011. View

19.

Zirakzadeh A, Sherif A, Rosenblatt R, Bergman E, Winerdal M, Yang D . Tumour-associated B cells in urothelial urinary bladder cancer. Scand J Immunol. 2019; 91(2):e12830. DOI: 10.1111/sji.12830. View

20.

Rosenberg J, Hoffman-Censits J, Powles T, van der Heijden M, Balar A, Necchi A . Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016; 387(10031):1909-20. PMC: 5480242. DOI: 10.1016/S0140-6736(16)00561-4. View