Liu et al. show that inhibition of TGFβ signaling in CD4+ T cells, but not CD8+ T cells, suppressed tumor growth in the PyMT model, independent of CD8+ T cell function. Loss of TGFBR2 in CD4+ T cells induced stromal localization of CD4+ T cells, vascular organization and maturation, and an increase in hypoxia and cancer cell death distal from the CD4+ cells. Tumor vasculature organization, hypoxia, and inhibition of cancer progression associated with TGFBR2-deficient CD4+ T cells was dependent on T helper 2 (TH2) cytokine IL-4, but not the TH1 cytokine IFNγ. An IL-4/TGFβ TH2 cell gene signature was associated with survival and disease aggressiveness.
Contributed by Shishir Pant
ABSTRACT: The immune system uses two distinct defence strategies against infections: microbe-directed pathogen destruction characterized by type 1 immunity(1), and host-directed pathogen containment exemplified by type 2 immunity in induction of tissue repair(2). Similar to infectious diseases, cancer progresses with self-propagating cancer cells inflicting host-tissue damage. The immunological mechanisms of cancer cell destruction are well defined(3-5), but whether immune-mediated cancer cell containment can be induced remains poorly understood. Here we show that depletion of transforming growth factor-β receptor 2 (TGFBR2) in CD4(+) T cells, but not CD8(+) T cells, halts cancer progression as a result of tissue healing and remodelling of the blood vasculature, causing cancer cell hypoxia and death in distant avascular regions. Notably, the host-directed protective response is dependent on the T helper 2 cytokine interleukin-4 (IL-4), but not the T helper 1 cytokine interferon-γ (IFN-γ). Thus, type 2 immunity can be mobilized as an effective tissue-level defense mechanism against cancer.
Author Info: (1) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Immunogenomics and Precision Oncology Platform (IPOP), Memorial Sl
Author Info: (1) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Immunogenomics and Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA. (6) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA. (9) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University, St Louis, MO, USA. (14) Immunogenomics and Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center, New York, NY, USA. Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. (16) Immunogenomics and Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. lim@mskcc.org. Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA. lim@mskcc.org. Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. lim@mskcc.org.
