The efficacy of PD-1 Checkpoint Blockade (ChB) as adjuvant therapy in localized clear cell Renal Cell Carcinoma (ccRCC) is currently unknown. The identification of tumor microenvironment (TME) prognostic biomarkers in this setting may help to define which patients could benefit from ChB and to uncover new therapeutic targets.
We performed multiparametric flow cytometry immunophenotypic analysis of T cells isolated from tumor tissue (TIL), adjacent non-malignant renal tissue (RIL) and peripheral blood (PBL), in a cohort of patients (n=40) with localized ccRCC. Immunophenotypic data was integrated with prognostic and histopathologic variables, TCR repertoire analysis of sorted CD8+PD-1+TIL, tumor mRNA expression and digital quantitative immunohistochemistry.
Based on TIL phenotypic characterization, we identified three dominant immune-profiles in localized ccRCC: 1) «Immune-regulated», characterized by polyclonal/poorly cytotoxic CD8+PD-1+Tim-3+Lag-3+ TIL and CD4+ICOS+ cells with a Treg phenotype (CD25+CD127-Foxp3+/Helios+GITR+), that developed in inflamed tumors with prominent infiltrations by dysfunctional dendritic cells and high PD-L1 expression; 2) «Immune-activated», enriched in oligoclonal/cytotoxic CD8+PD-1+Tim-3+ TIL, that represented 22% of the tumors; and 3) «Immune-silent», enriched in TIL exhibiting RIL-like phenotype, that represented 56% of patients in the cohort. Only «Immune-regulated» tumors displayed aggressive histologic features, high risk of disease progression in the year following nephrectomy, and a CD8+PD-1+Tim-3+ and CD4+ICOS+ PBL phenotypic signature.
In localized ccRCC, the infiltration with CD8+PD-1+Tim3+Lag-3+ exhausted TIL and ICOS+Treg identifies the patients with deleterious prognosis, who could benefit from adjuvant therapy with TME-modulating agents and ChB. This work also provides PBL phenotypic markers that could allow their identification.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2017 Feb 17 [Epub ahead of print]
Nicolas A Giraldo, Etienne Becht, Yann Vano, Florent Petitprez, Laetitia Lacroix, Pierre Validire, Rafael Sanchez-Salas, Alexandre Ingels, Stephane Marie Oudard, Audrey Moatti, Bénédicte Buttard, Sarah Bourras, Claire Germain, Xavier Cathelineau, Wolf-Herman Fridman, Catherine Sautes-Fridman
Equipe 13, Centre de Recherche des Cordeliers., Centre de Recherche de Cordelier., Pathology, Institut Montsouris., Urology, Institute Montsouris., Urology, Stanford University., Medical Oncology, Hopital Européen Georges Pompidou., Centre de Recherche des Cordeliers, INSERM UMRS 1138., UMRS1138, Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale (INSERM)., urology, institut montsouris., Laboratoire Cancer, Immune control and escape, Centre de Recherche des Cordeliers, Inserm UMRS 1138 .