A GATA4-regulated secretory program suppresses tumors through recruitment of cytotoxic CD8 T cells
Name
s41467-021-27731-5.pdf
Description
Published version
Size
1.97 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Patel, Rupesh S
Romero, Rodrigo
Watson, Emma V
Liang, Anthony C
Burger, Megan
Westcott, Peter MK
Mercer, Kim L
Bronson, Roderick T
Wooten, Eric C
Bhutkar, Arjun
Date Issued
2022
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Patel, Rupesh S, Romero, Rodrigo, Watson, Emma V, Liang, Anthony C, Burger, Megan et al. 2022. "A GATA4-regulated secretory program suppresses tumors through recruitment of cytotoxic CD8 T cells." Nature Communications, 13 (1).
Version
Final published version
Abstract
AbstractThe 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41467-021-27731-5
