Tsai et al. showed that exposure to INFγ during early-stage T cell-mediated immunosurveillance remodeled the epigenetic and transcriptional landscape of the tumor cells to facilitate a switch from OXPHOS toward aerobic glycolysis, and promoted tumor immune evasion. The IFNγ–STAT3 signaling axis promoted cMyc-dependent metabolic reprogramming and resistance to senescence. In vivo CRISPR screening identified metabolic pathways regulating the antitumor immunity and identified Fasn and Slc23a2 as potential targets to suppress cMyc-mediated metabolic reprogramming and immune evasion.
Contributed by Shishir Pant
ABSTRACT: Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment.
Author Info: (1) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland; Graduate Institute of
Author Info: (1) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei City, Taiwan. (2) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland. (3) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland. (4) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland. (5) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei City, Taiwan. (6) Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA. (7) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Laboratory of Tumor Inflammation and angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium; Laboratory of Tumor Inflammation and angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium. (9) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland. (10) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland. (11) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland. (12) CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Wien, Austria. (13) Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, USA. (14) Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. (15) Agricultural Biotechnology Research Center, Academia Sinica, Taipei City, Taiwan. (16) Laboratory of Tumor Inflammation and angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium; Laboratory of Tumor Inflammation and angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium. (17) CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Wien, Austria. (18) Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, USA. (19) Division of Tumor Biology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands. (20) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, USA. (21) Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA; Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI, USA. (22) NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA. (23) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute of Cancer Research, University of Lausanne, Lausanne, Switzerland. Electronic address: ping-chih.ho@unil.ch.
