CD8+ Cytotoxic Immune Infiltrate in Non-Muscle Invasive Bladder Cancer: A Standardized Methodology to Study Association with Clinico-Pathological Features and Prognosis

Masson-Lecomte A, Maille P, Pineda S, Soyeux P, Sagrera A, Rava M, Lopez De Maturana E, Marquez M, Tardon A, Carrato A, Kogevinas M, De La Taille A, Hartmann A, Malats N, Real P, Allory Y (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Bladder Cancer IOS Press

Book Volume: 5

Pages Range: 159-169

Journal Issue: 2

DOI: 10.3233/BLC-180206

Abstract

Background: Major interest lies in the evaluation of immune infiltrate in bladder cancer. CD8+ cytotoxic lymphocytes are key effectors of adaptive immune response. Objectives: The aims of the study were to set up a standardized methodology for CD8+ lymphocytes estimation in NMIBC and investigate how intra-tumoral heterogeneity influences CD8+ immune infiltrate. Methods: We considered 995 NMIBC included in the Spanish Bladder Cancer (SBC)/EPICURO Study. Duplicate 0.6mm TMA spots and paired full sections (FS) for 50 selected cases were double stained with anti-pan cytokeratin antibody and anti-CD8 antibody. Slides were digitalized and CD8+ cells were automatically counted after tissue recognition (tumor vs stroma). Spatial heterogeneity was assessed and a resampling strategy was applied to estimate the proper number of 0.6mm TMA spots providing an adequate CD8+ cell estimate. Association between CD8+ count and expression of urothelial differentiation markers was estimated. Cox regression models were performed to assess association between CD8+ cell count and risk of recurrence and progression. Results: Microscopic examination of full sections showed spatial heterogeneity for CD8+ infiltrates. Simulation analyses demonstrated that 5 TMA regions provided a correct sampling of tumor and stromal compartments in Ta while 2 and 6 TMA regions were necessary in T1, respectively. CD8+ cells infiltration was associated with stage, regardless of the histological compartment analyzed (median CD8+/mm2 were 25/mm2 and 129/mm2 in tumor and stroma respectively in Ta and 111/mm2 and 344/mm2 in T1; p-value=0.006). CD8+ infiltration in tumor compartment was significantly associated with low FGFR3 expression. CD8+/mm2 count in the tumor compartment was not associated with prognosis. Conclusion: Differences identified between Ta and T1 tumours supported the hypothesis that rigorous efforts should be placed in proper study design. These results provide a new framework to investigate microenvironment complexity in bladder cancer.

Authors with CRIS profile

Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie

Involved external institutions

Centro de Investigación Biomédica en Red (CIBER) ES Spain (ES) IMIM: Institut Hospital del Mar d'Investigacions Mèdiques ES Spain (ES) Centre hospitalier universitaire Henri-Mondor (CHU Henri-Mondor) FR France (FR) University of Paris 7 - Denis Diderot / Université Paris VII Denis Diderot FR France (FR) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) ES Spain (ES) Institut Curie FR France (FR) Universidad de Oviedo ES Spain (ES)

How to cite

APA:

Masson-Lecomte, A., Maille, P., Pineda, S., Soyeux, P., Sagrera, A., Rava, M.,... Allory, Y. (2019). CD8+ Cytotoxic Immune Infiltrate in Non-Muscle Invasive Bladder Cancer: A Standardized Methodology to Study Association with Clinico-Pathological Features and Prognosis. Bladder Cancer, 5(2), 159-169. https://doi.org/10.3233/BLC-180206

MLA:

Masson-Lecomte, Alexandra, et al. "CD8+ Cytotoxic Immune Infiltrate in Non-Muscle Invasive Bladder Cancer: A Standardized Methodology to Study Association with Clinico-Pathological Features and Prognosis." Bladder Cancer 5.2 (2019): 159-169.

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