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

Authors

Susana Castro-Pando
Rian M Howell
Le Li
Marilina Mascaro
Erika Y Faraoni
Olivereen Le Roux
David Romanin
Virginia Tahan
Erick Riquelme
Yu Zhang
Jay K Kolls
James P Allison
Guillermina Lozano
Seyed J Moghaddam
Florencia McAllister

Publication Date

9-3-2024

Journal

Cancer Immunology Research

Abstract

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.

Keywords

Animals, Interleukin-17, Pancreatic Neoplasms, Receptors, Interleukin-17, Mice, Signal Transduction, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Tumor Microenvironment, Carcinogenesis, Mice, Transgenic, Humans, Epithelial Cells, Mice, Knockout, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Cell Transformation, Neoplastic, Pancreas

Comments

Supplementary Materials

PMID: 38842383