Immune in filtrates are prognostic factors in localized gastrointestinal stromal tumors

Sylvie Rusakiewicz, Michaela Semeraro, Matthieu Sarabi, Mélanie Desbois, Clara Locher, Rosa Mendez, Nadège Vimond, Angel Concha, Federico Garrido, Nicolas Isambert, Loic Chaigneau, Valérie Le Brun-Ly, Patrice Dubreuil, Isabelle Cremer, Anne Caignard, Vichnou Poirier-Colame, Kariman Chaba, Caroline Flament, Niels Halama, Dirk Jag̈erAlexander Eggermont, Sylvie Bonvalot, Fréd́eric Commo, Philippe Terrier, Paule Opolon, Jean François Emile, Jean Michel Coindre, Guido Kroemer, Nathalie Chaput, Axel Le Cesne, Jean Yves Blay, Laurence Zitvogel

Research output: Contribution to journalArticlepeer-review

254 Citations (Scopus)

Abstract

Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8+ T cells with a T-helper cell 1 (T H 1) pro fi le. Evidence for a natural killer (NK) cell-based control of humanmalignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes (TIL) expressing CD3, Foxp3, or NKp46 (NCR1) ina cohort of patients with localized GIST.We found that CD3+TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class IMHC expression despite imatinib mesylate treatment. High densities of CD3 + TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokine-secreting CD56bright (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK in fi ltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratifi cation of patients with GIST.

Original languageEnglish
Pages (from-to)3499-3510
Number of pages12
JournalCancer Research
Volume73
Issue number12
DOIs
Publication statusPublished - 15 Jun 2013
Externally publishedYes

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