Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis.

Autor:	Castro-Pando S; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas., Howell RM; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Li L; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Mascaro M; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.; CONICET, Buenos Aires, Argentina., Faraoni EY; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Le Roux O; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Romanin D; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Tahan V; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Riquelme E; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas., Zhang Y; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas., Kolls JK; Department of Medicine and Pediatrics, Tulane School of Medicine, New Orleans, Louisiana., Allison JP; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lozano G; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas., Moghaddam SJ; Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas., McAllister F; Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2024 Sep 03; Vol. 12 (9), pp. 1170-1183.
DOI:	10.1158/2326-6066.CIR-23-0527
Abstrakt:	IL17 is required for the initiation and progression of pancreatic cancer, particularly in the context of inflammation, as previously shown by genetic and pharmacological approaches. However, the cellular compartment and downstream molecular mediators of IL17-mediated pancreatic tumorigenesis have not been fully identified. This study examined the cellular compartment required by generating transgenic animals with IL17 receptor A (IL17RA), which was genetically deleted from either the pancreatic epithelial compartment or the hematopoietic compartment via generation of IL17RA-deficient (IL17-RA-/-) bone marrow chimeras, in the context of embryonically activated or inducible Kras. Deletion of IL17RA from the pancreatic epithelial compartment, but not from hematopoietic compartment, resulted in delayed initiation and progression of premalignant lesions and increased infiltration of CD8+ cytotoxic T cells to the tumor microenvironment. Absence of IL17RA in the pancreatic compartment affected transcriptional profiles of epithelial cells, modulating stemness, and immunological pathways. B7-H4, a known inhibitor of T-cell activation encoded by the gene Vtcn1, was the checkpoint molecule most upregulated via IL17 early during pancreatic tumorigenesis, and its genetic deletion delayed the development of pancreatic premalignant lesions and reduced immunosuppression. Thus, our data reveal that pancreatic epithelial IL17RA promotes pancreatic tumorigenesis by reprogramming the immune pancreatic landscape, which is partially orchestrated by regulation of B7-H4. Our findings provide the foundation of the mechanisms triggered by IL17 to mediate pancreatic tumorigenesis and reveal the avenues for early pancreatic cancer immune interception. See related Spotlight by Lee and Pasca di Magliano, p. 1130. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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