Journal
ONCOIMMUNOLOGY
Volume 6, Issue 2, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2016.1271858
Keywords
Antitumor cytotoxic response; CTL; EMT; hypoxia; HIF; NSCLC; NK cells; TGF-beta
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Funding
- Institute of Molecular Cell Biology (core funding A*STAR, Singapore, JPT)
- Ligue contre le Cancer (equipe labellisee, SC)
- Institut National du Cancer and Gustave Roussy [INCa PLBIO15-266]
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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 (EMTTFs) SNAI1, SNAI2, TWIST1, and ZEB2 in a hypoxia-inducible factor-1a (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-b signaling, attenuated mesenchymal subclone susceptibility to immune attack. Together, these findings uncover hypoxiainduced EMT and heterogeneity as a novel driving escape mechanism to lymphocyte-mediated cytotoxicity, with the potential to provide new therapeutic opportunities for cancer patients.
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