title: Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma.
abstract: Purpose:The efficacy of PD-1 checkpoint blockade 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 define which patients could benefit from checkpoint blockade and uncover new therapeutic targets.Experimental Design:We performed multiparametric flow cytometric immunophenotypic analysis of T cells isolated from tumor tissue [tumor-infiltrating lymphocytes (TIL)], adjacent non-malignant renal tissue [renal-infiltrating lymphocytes (RIL)], and peripheral blood lymphocytes (PBL), in a cohort of patients (n= 40) with localized ccRCC. Immunophenotypic data were integrated with prognostic and histopathologic variables, T-cell receptor (TCR) repertoire analysis of sorted CD8+PD-1+TILs, tumor mRNA expression, and digital quantitative immunohistochemistry.Results:On the basis of TIL phenotypic characterization, we identified three dominant immune profiles in localized ccRCC: (i) immune-regulated, characterized by polyclonal/poorly cytotoxic CD8+PD-1+Tim-3+Lag-3+TILs 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; (ii) immune-activated, enriched in oligoclonal/cytotoxic CD8+PD-1+Tim-3+TILs, that represented 22% of the tumors; and (iii) immune-silent, enriched in TILs 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.Conclusions:In localized ccRCC, the infiltration with CD8+PD-1+Tim-3+Lag-3+exhausted TILs and ICOS+Treg identifies the patients with deleterious prognosis who could benefit from adjuvant therapy with TME-modulating agents and checkpoint blockade. This work also provides PBL phenotypic markers that could allow their identification.Clin Cancer Res; 23(15); 4416-28. ©2017 AACR.
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Giraldo
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Becht
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|Georges Pompidou European Hospital, Oncology Department, Paris 5 - Descartes University, Assistance Publique Hopitaux de Paris, Paris, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Vano
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|Carte d'Identité des Tumeurs, Ligue contre le Cancer, Paris, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Petitprez
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: Pathology Department, Institut Mutualiste Montsouris, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Validire
authors.affiliation: Urology Department, Institut Mutualiste Montsouris, Paris, France.
authors.forename: Rafael
authors.initials: R
authors.lastname: Sanchez-Salas
authors.affiliation: Urology Department, Institut Mutualiste Montsouris, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ingels
authors.affiliation: Georges Pompidou European Hospital, Oncology Department, Paris 5 - Descartes University, Assistance Publique Hopitaux de Paris, Paris, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Oudard
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Moatti
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Buttard
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bourass
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Germain
authors.affiliation: Urology Department, Institut Mutualiste Montsouris, Paris, France.|University Paris Descartes Paris, Medical School, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Cathelineau
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France. catherine.fridman@crc.jussieu.fr herve.fridman@crc.jussieu.fr.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Wolf H
authors.initials: WH
authors.lastname: Fridman
authors.affiliation: INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France. catherine.fridman@crc.jussieu.fr herve.fridman@crc.jussieu.fr.|University Paris Descartes Paris, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|UPMC University Paris, Sorbonne University, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sautès-Fridman
mesh_terms: D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins