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

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.

SUBMITTER: Patel RS

PROVIDER: S-EPMC8752777 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Patel Rupesh S RS Romero Rodrigo R Watson Emma V EV Liang Anthony C AC Burger Megan M Westcott Peter M K PMK Mercer Kim L KL Bronson Roderick T RT Wooten Eric C EC Bhutkar Arjun A Jacks Tyler T Elledge Stephen J SJ

Nature communications 20220111 1

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 ...[more]

PMID: 35017504

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Project description:BackgroundThe IL-17 family cytokines are potent drivers of colorectal cancer (CRC) development. We and others have shown that IL-17 mainly signals to tumor cells to promote CRC, but the underlying mechanism remains unclear. IL-17 also dampens Th1-armed anti-tumor immunity, in part by attracting myeloid cells to tumor. Whether IL-17 controls the activity of adaptive immune cells in a more direct manner, however, is unknown.MethodsUsing mouse models of sporadic or inducible colorectal cancers, we ablated IL-17RA in the whole body or specifically in colorectal tumor cells. We also performed adoptive bone marrow reconstitution to knockout CXCR3 in hematopoietic cells. Histological and immunological experimental methods were used to reveal the link among IL-17, chemokine production, and CRC development.ResultsLoss of IL-17 signaling in mouse CRC resulted in marked increase in the recruitment of CD8+ cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs), starting from early stage CRC lesions. This is accompanied by the increased expression of anti-inflammatory cytokines IL-10 and TGF-β. IL-17 signaling also inhibits the production of T cell attracting chemokines CXCL9 and CXCL10 by tumor cells. Conversely, the inability of hematopoietic cells to respond to CXCL9/10 resulted in decreased tumor infiltration by CTLs and Tregs, decreased levels of IL-10 and TGF-β, and increased numbers of tumor lesions. Blockade of IL-17 signaling resulted in increased expression of immune checkpoint markers. On the other hand, treatment of mouse CRC with anti-CTLA-4 antibody led to increased expression of pro-tumor IL-17.ConclusionIL-17 signals to colorectal tumor cells and inhibits their production of CXCL9/10 chemokines. By doing so, IL-17 inhibits the infiltration of CD8+ CTLs and Tregs to CRC, thus promoting CRC development. Cancer immunotherapy may be benefited by the use of anti-IL-17 agents as adjuvant therapies, which serve to block both IL-17-mediated tumor promotion and T cell exclusion.

Project description:BackgroundHypoxia in tumor cells is linked to increased drug resistance and more aggressive behavior. In pancreatic cancer, the tumor microenvironment is notably hypoxic and exhibits strong immunosuppressive properties. Given that immunotherapy is now approved for pancreatic cancer treatment, further understanding of how pancreatic tumor cell hypoxia influences T-cell cytotoxicityis essential.ObjectiveThis study examined how hypoxia affects the interaction between pancreatic tumor cells (PANC-1) and cytotoxic CD8+ T-cells.MethodsPancreatic tumor cells (PANC-1) were exposed to 20 cycles of chronic hypoxic conditions, each for 72 hours, followed by a re-oxygenation period for 24 hours. On cycles 10 and 20, PANC-1 conditioned media (CM) was harvested, and the hypoxic PANC-1 cells were co-cultured with either the activated cytotoxic CD8+ T-cells or with CD8+ T-cells CM. CD8+ T-cells CM was collected after five days of cell activation using anti-CD3/CD28 antibodies and interleukin-2 (IL-2). CD8+ T-cells were activated for 72 hours and then cultured with the hypoxic PANC-1 CM.ResultsHypoxic PANC-1 cells showed significant resistance to the lytic effect of either CD8+ T-cells co-culture or CD8+ T-cells CM treatment compared to normoxic PANC-1 cells. A significant decrease in TNF-α and IFN-γ levels was also detected. Additionally, a significant increase in IL-6, p53 and TNF-α gene expression levels was observed in PANC-1 cells treated with CD8+ T-cells CM. Moreover, IL-6 gene expression level showed a significant difference between hypoxic and normoxic PANC-1 cells. CD8+ T-cell proliferation and cytokines production were significantly higher in cells co-cultured with PANC-1 CM. However, no significant differences were observed after treatment with either hypoxic or normoxic PANC-1 CM.ConclusionHypoxia decreases PANC-1 cells' sensitivity to cytotoxic CD8+ T-cells. Reduced tumor cell susceptibility to CD8+ T-cells was associated with increased IL-6 expression and reduced TNF-α and IFN-γ levels. Thus, cytokine dysregulation might contribute to the hypoxia-mediated resistance of pancreatic tumor cells to CD8+ T-cells.

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

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

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