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

Emma V Watson,Eric C Wooten,Roderick T Bronson,Megan Burger,Rodrigo Romero,Peter M K Westcott,Rupesh S Patel,Anthony C Liang,Stephen J Elledge,Kim L Mercer,Arjun Bhutkar,Tyler Jacks

doi:10.1038/s41467-021-27731-5

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.

Highlights

The GATA-binding protein 4 (GATA4) transcription factor acts as a master regulator of development of multiple tissues
Immunohistochemistry of phospho-Histone H3, a marker of proliferation, was reduced in sgRNAs targeting Gata4 (sgGata4)-targeted tumors when compared to sgCtrl mice at the 16-week timepoint and trended downward at the 8-week timepoint, suggesting overall that an increase in tumor burden in sgGata[4] mice was not due to an increase in cell cycle activity (Fig. 1i, Supplementary Fig. 1e)
GATA4 is frequently lost in human cancer and our analyses found that GATA4 copy number is positively correlated with the number of TILs in multiple human tumor types

Summary

Introduction

The GATA4 transcription factor acts as a master regulator of development of multiple tissues. GATA4 acts in a distinct capacity to control a stress-inducible pro-inflammatory secretory program that is associated with senescence, a potent tumor suppression mechanism, and operates in non-senescent contexts such as tumorigenesis. This secretory pathway is composed of chemokines, cytokines, growth factors, and proteases. While senescence-associated, the term SASP is somewhat imprecise in the sense that it happens to be activated by similar stresses but can be activated in replicating cells independently of the cell cycle arrest pathways that are required for senescence This secretory response to DNA damage can be genetically separated from the mitotic arrest in senescent cells by mutation of the GATA-binding protein 4 (GATA4) transcription factor. We found that GATA4 regulates the expression of a secretory program that suppresses tumorigenesis through the recruitment of CD8 T cells

Methods

Results

Conclusion