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A GATA4-regulated secretory program suppresses tumors through recruitment of cytotoxic CD8 T cells

Author

Listed:
  • Rupesh S. Patel

    (Brigham and Women’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute
    Scripps Green Hospital)

  • Rodrigo Romero

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center)

  • Emma V. Watson

    (Brigham and Women’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute)

  • Anthony C. Liang

    (Brigham and Women’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute)

  • Megan Burger

    (Massachusetts Institute of Technology)

  • Peter M. K. Westcott

    (Massachusetts Institute of Technology)

  • Kim L. Mercer

    (Massachusetts Institute of Technology)

  • Roderick T. Bronson

    (Harvard Medical School)

  • Eric C. Wooten

    (Brigham and Women’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute)

  • Arjun Bhutkar

    (Massachusetts Institute of Technology)

  • Tyler Jacks

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Stephen J. Elledge

    (Brigham and Women’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute)

Abstract

The GATA4 transcription factor acts as a master regulator of development of multiple tissues. GATA4 also acts in a distinct capacity to control a stress-inducible pro-inflammatory secretory program that is associated with senescence, a potent tumor suppression mechanism, but also operates in non-senescent contexts such as tumorigenesis. This secretory pathway is composed of chemokines, cytokines, growth factors, and proteases. Since GATA4 is deleted or epigenetically silenced in cancer, here we examine the role of GATA4 in tumorigenesis in mouse models through both loss-of-function and overexpression experiments. We find that GATA4 promotes non-cell autonomous tumor suppression in multiple model systems. Mechanistically, we show that Gata4-dependent tumor suppression requires cytotoxic CD8 T cells and partially requires the secreted chemokine CCL2. Analysis of transcriptome data in human tumors reveals reduced lymphocyte infiltration in GATA4-deficient tumors, consistent with our murine data. Notably, activation of the GATA4-dependent secretory program combined with an anti-PD-1 antibody robustly abrogates tumor growth in vivo.

Suggested Citation

  • Rupesh S. Patel & Rodrigo Romero & Emma V. Watson & Anthony C. Liang & Megan Burger & Peter M. K. Westcott & Kim L. Mercer & Roderick T. Bronson & Eric C. Wooten & Arjun Bhutkar & Tyler Jacks & Stephe, 2022. "A GATA4-regulated secretory program suppresses tumors through recruitment of cytotoxic CD8 T cells," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27731-5
    DOI: 10.1038/s41467-021-27731-5
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