title: Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors.
abstract: Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8(+) T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies 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) in a 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 I MHC 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 CD56(bright) (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK infiltrate 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 stratification of patients with GIST.
authors.affiliation: Institut Gustave Roussy; Institut National de la Santé et de la Recherche Medicale (INSERM) U1015, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rusakiewicz
authors.forename: Michaela
authors.initials: M
authors.lastname: Semeraro
authors.forename: Matthieu
authors.initials: M
authors.lastname: Sarabi
authors.forename: Mélanie
authors.initials: M
authors.lastname: Desbois
authors.forename: Clara
authors.initials: C
authors.lastname: Locher
authors.forename: Rosa
authors.initials: R
authors.lastname: Mendez
authors.forename: Nadège
authors.initials: N
authors.lastname: Vimond
authors.forename: Angel
authors.initials: A
authors.lastname: Concha
authors.forename: Federico
authors.initials: F
authors.lastname: Garrido
authors.forename: Nicolas
authors.initials: N
authors.lastname: Isambert
authors.forename: Loic
authors.initials: L
authors.lastname: Chaigneau
authors.forename: Valérie
authors.initials: V
authors.lastname: Le Brun-Ly
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cremer
authors.forename: Anne
authors.initials: A
authors.lastname: Caignard
authors.forename: Vichnou
authors.initials: V
authors.lastname: Poirier-Colame
authors.forename: Kariman
authors.initials: K
authors.lastname: Chaba
authors.forename: Caroline
authors.initials: C
authors.lastname: Flament
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bonvalot
authors.forename: Frédéric
authors.initials: F
authors.lastname: Commo
authors.forename: Philippe
authors.initials: P
authors.lastname: Terrier
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000276:immunology / Q000627:therapeutic use; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D019002:CD56 Antigen / Q000276:immunology / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000276:immunology / Q000378:metabolism; D010879:Piperazines / Q000276:immunology / Q000627:therapeutic use; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000276:immunology / Q000627:therapeutic use; D011743:Pyrimidines / Q000276:immunology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D017252:CD3 Complex; D019002:CD56 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C522918:NCAM1 protein, human; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate