Pancreatic cancer cells assemble a CXCL12-keratin 19 coating to resist immunotherapy

Wang, Zhikai, Yan, Ran, Li, Jiayun, Gao, Ya, Moresco, Philip, Yao, Min, Hechtman, Jaclyn F, Weiss, Matthew J, Janowitz, Tobias, Fearon, Douglas T (September 2020) Pancreatic cancer cells assemble a CXCL12-keratin 19 coating to resist immunotherapy. bioRxiv. (Unpublished)

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Abstract

How pancreatic ductal adenocarcinoma (PDA) cells stimulate CXCR4 to exclude T cells and resist T cell checkpoint inhibitors is not known. Here, we find that CXCL12, the ligand for CXCR4 that is produced by the cancer-associated fibroblast, “coats” human PDA and colorectal cancer cells as covalent heterodimers with keratin 19 (KRT19). Modeling the formation of the heterodimer with three proteins shows that KRT19 binds CXCL12 and transglutaminase-2 (TGM2), and that TGM2 converts the reversible KRT19-CXCL12 complex into a covalent heterodimer. We validate this model by showing that cancer cells in mouse PDA tumors must express KRT19 and TGM2 to become coated with CXCL12, exclude T cells, and resist immunotherapy with anti-PD-1 antibody. Thus, PDA cells have a cell-autonomous means by which they capture CXCL12 to mediate immune suppression, which is potentially amenable to therapy. One Sentence Summary Cancer cells in pancreatic ductal adenocarcinoma use transglutaminase-2 to assemble a coating comprised of covalent CXCL12-keratin 19 heterodimers that excludes T cells and mediates resistance to inhibition of the PD-1 T cell checkpoint.

Item Type:	Paper
Subjects:	diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:	Wang, Zhikai Yan, Ran Li, Jiayun Janowitz, Tobias Fearon, Douglas Gao, Ya Moresco, Philip Yao, Min
Communities:	CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Fearon lab CSHL labs > Janowitz lab School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	4 September 2020
Date Deposited:	14 Jul 2021 13:52
Last Modified:	29 Feb 2024 19:26
URI:	https://repository.cshl.edu/id/eprint/40288

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