title: Early Effector T Lymphocytes Coexpress Multiple Inhibitory Receptors in Primary Non-Small Cell Lung Cancer.
abstract: Clinical efficacy of PD-1/PD-L1 targeting relies upon the reactivation of tumor-specific but functionally impaired PD-1+T cells present before therapy. Thus, analyzing early-stage primary tumors may reveal the presence of T cells that are not yet functionally impaired. In this study, we report that activated (HLA-DR+) T cells with an effector memory (TEM) profile are enriched in such lesions. Tumor-infiltrating lymphocytes coexpressed PD-1 with the inhibitory receptors TIM-3, CTLA-4, LAG-3, and TIGIT, but also displayed a recently activated, nonexhausted phenotype. We also identified a subset of CD8+PD-1+FOXP3+T lymphocytes at the earliest phase of functional differentiation after priming, termed "early effector cells" (EEC), which also exhibited an activated nonexhausted phenotype, but was less differentiated and associated with coexpression of multiple inhibitory receptors. In response to autologous tumor, EECs upregulated CD107a, produced IL2 and IFNγ, and were competent for differentiation. The identification of EECs marked by inhibitory receptor expression at tumor sites will enable investigations of early stages of adaptive antitumor immunity, as well as support the rationale for administering immunotherapy in early-stage non-small cell lung cancer.Cancer Res; 77(4); 851-61. ©2016 AACR.
authors.affiliation: Human Tumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tassi
authors.affiliation: Human Tumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Grazia
authors.affiliation: Human Tumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vegetti
authors.affiliation: Human Tumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bersani
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bertolini
authors.affiliation: Human Tumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Molla
authors.affiliation: Human Tumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Baldassari
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Andriani
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Roz
authors.affiliation: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
authors.affiliation: Unit of Thoracic Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Pastorino
authors.affiliation: Human Tumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Mortarini
authors.affiliation: Human Tumors Immunobiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. andrea.anichini@istitutotumori.mi.it elena.tassi@istitutotumori.mi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Anichini
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000032:analysis; D006684:HLA-DR Antigens / Q000032:analysis; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000032:analysis; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000276:immunology*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis; D011971:Receptors, Immunologic / Q000032:analysis; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C448908:HAVCR2 protein, human; D006684:HLA-DR Antigens; D000072597:Hepatitis A Virus Cellular Receptor 2; C508594:IL2 protein, human; D007376:Interleukin-2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; C534712:TIGIT protein, human; D007371:Interferon-gamma; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human