Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicity

• Main Authors: Stéphane Terry, Stéphanie Buart, Tuan Zea Tan, Gwendoline Gros, Muhammad Zaeem Noman, James B. Lorens, Fathia Mami-Chouaib, Jean Paul Thiery, Salem Chouaib
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2017-02-01
• Series: OncoImmunology
• Subjects: antitumor cytotoxic response; ctl; emt; hypoxia; hif; nsclc; nk cells; tgf-β
• Online Access: http://dx.doi.org/10.1080/2162402X.2016.1271858

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.