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

Rupesh S Patel1,2,3,4, Rodrigo Romero5,6,7, Emma V Watson1,2,3

  • 1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Nature Communications
|January 12, 2022
PubMed

Insights

The GATA4 transcription factor suppresses tumors by activating a secretory program that recruits immune cells. Activating this pathway with an anti-PD-1 antibody halts tumor growth, offering a potential cancer therapy.

Area of Science:

  • Molecular Biology
  • Immunology
  • Oncology

Background:

  • GATA4 is a key developmental regulator that also controls a pro-inflammatory secretory program.
  • This program is linked to senescence and tumorigenesis, and GATA4 is often lost in cancer.
  • The role of GATA4 in tumor suppression and its underlying mechanisms remain unclear.

Purpose of the Study:

  • To investigate the role of GATA4 in tumorigenesis using mouse models.
  • To elucidate the mechanisms by which GATA4 influences tumor suppression.
  • To explore therapeutic strategies targeting the GATA4-dependent secretory pathway.

Main Methods:

  • Loss-of-function and overexpression experiments in mouse models of tumorigenesis.
  • Analysis of Gata4-dependent secretory pathways, including chemokines like CCL2.
  • Assessment of immune cell involvement, particularly CD8 T cells.
  • Transcriptome analysis of human tumors and in vivo efficacy studies of combined therapy.

Main Results:

  • GATA4 was found to promote non-cell autonomous tumor suppression across multiple models.
  • Gata4-dependent tumor suppression necessitates cytotoxic CD8 T cells and is partially dependent on CCL2.
  • Human tumors lacking GATA4 show reduced lymphocyte infiltration, mirroring murine findings.
  • Combining GATA4-secretory program activation with anti-PD-1 therapy effectively inhibited tumor growth.

Conclusions:

  • GATA4 functions as a non-cell autonomous tumor suppressor.
  • The GATA4-dependent secretory program, involving CD8 T cells and CCL2, is crucial for tumor suppression.
  • Targeting the GATA4 pathway in combination with immunotherapy presents a promising strategy for cancer treatment.

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