Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicity
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...
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doaj-70fbd55ee95a46119b64c9bcf3122bd12020-11-25T02:51:19ZengTaylor & Francis GroupOncoImmunology2162-402X2017-02-016210.1080/2162402X.2016.12718581271858Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicityStéphane Terry0Stéphanie Buart1Tuan Zea Tan2Gwendoline Gros3Muhammad Zaeem Noman4James B. Lorens5Fathia Mami-Chouaib6Jean Paul Thiery7Salem Chouaib8INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine – Univ. Paris-Sud, University Paris-SaclayINSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine – Univ. Paris-Sud, University Paris-SaclayCancer Science Institute of Singapore, National University of SingaporeINSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine – Univ. Paris-Sud, University Paris-SaclayINSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine – Univ. Paris-Sud, University Paris-SaclayUniversity of BergenINSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine – Univ. Paris-Sud, University Paris-SaclayINSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine – Univ. Paris-Sud, University Paris-SaclayINSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Fac. de médecine – Univ. Paris-Sud, University Paris-SaclayTumor 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.http://dx.doi.org/10.1080/2162402X.2016.1271858antitumor cytotoxic responsectl emthypoxiahifnsclcnk cellstgf-β |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Stéphane Terry Stéphanie Buart Tuan Zea Tan Gwendoline Gros Muhammad Zaeem Noman James B. Lorens Fathia Mami-Chouaib Jean Paul Thiery Salem Chouaib |
spellingShingle |
Stéphane Terry Stéphanie Buart Tuan Zea Tan Gwendoline Gros Muhammad Zaeem Noman James B. Lorens Fathia Mami-Chouaib Jean Paul Thiery Salem Chouaib Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicity OncoImmunology antitumor cytotoxic response ctl emt hypoxia hif nsclc nk cells tgf-β |
author_facet |
Stéphane Terry Stéphanie Buart Tuan Zea Tan Gwendoline Gros Muhammad Zaeem Noman James B. Lorens Fathia Mami-Chouaib Jean Paul Thiery Salem Chouaib |
author_sort |
Stéphane Terry |
title |
Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicity |
title_short |
Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicity |
title_full |
Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicity |
title_fullStr |
Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicity |
title_full_unstemmed |
Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicity |
title_sort |
acquisition of tumor cell phenotypic diversity along the emt spectrum under hypoxic pressure: consequences on susceptibility to cell-mediated cytotoxicity |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2017-02-01 |
description |
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. |
topic |
antitumor cytotoxic response ctl emt hypoxia hif nsclc nk cells tgf-β |
url |
http://dx.doi.org/10.1080/2162402X.2016.1271858 |
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