title: Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicity.
abstract: Tumor escape to immunosurveillance and resistance to immune attacks present a major hurdle in cancer therapy, especially in the current era of new cancer immunotherapies. We report here that hypoxia, a hallmark of most solid tumors, orchestrates carcinoma cell heterogeneity through the induction of phenotypic diversity and the acquisition of distinct epithelial-mesenchymal transition (EMT) states. Using lung adenocarcinoma cells derived from a non-metastatic patient, we demonstrated that hypoxic stress induced phenotypic diversity along the EMT spectrum, with induction of EMT transcription factors (EMT-TFs) SNAI1, SNAI2, TWIST1, and ZEB2 in a hypoxia-inducible factor-1α (HIF1A)-dependent or -independent manner. Analysis of hypoxia-exposed tumor subclones, with pronounced epithelial or mesenchymal phenotypes, revealed that mesenchymal subclones exhibited an increased propensity to resist cytotoxic T lymphocytes (CTL), and natural killer (NK) cell-mediated lysis by a mechanism involving defective immune synapse signaling. Additionally, targeting EMT-TFs, or inhibition of TGF-β signaling, attenuated mesenchymal subclone susceptibility to immune attack. Together, these findings uncover hypoxia-induced EMT and heterogeneity as a novel driving escape mechanism to lymphocyte-mediated cytotoxicity, with the potential to provide new therapeutic opportunities for cancer patients.
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, University Paris-Saclay , Villejuif, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Terry
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, University Paris-Saclay , Villejuif, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Buart
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore , Singapore.
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, University Paris-Saclay , Villejuif, France.
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Gros
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, University Paris-Saclay, Villejuif, France; Laboratory of Experimental Cancer Research, Department of Oncology, Luxembourg Institute of Health (L.I.H), Luxembourg, Luxembourg.
authors.forename: Muhammad Zaeem
authors.initials: MZ
authors.lastname: Noman
authors.affiliation: Department of Biomedicine, University of Bergen , Bergen, Norway.
authors.forename: James B
authors.initials: JB
authors.lastname: Lorens
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, University Paris-Saclay , Villejuif, France.
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, University Paris-Saclay, Villejuif, France; Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A-STAR, Singapore.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine - Univ. Paris-Sud, University Paris-Saclay , Villejuif, France.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
keywords:  EMT; Antitumor cytotoxic response; CTL; HIF; NK cells; NSCLC; TGF-β; hypoxia