Transglutaminase-2 of pancreatic cancer cells assembles a CXCL12-keratin 19-coat that mediates the resistance to immunotherapy

To enhance efficacy of cancer immunotherapy, we must discover how adenocarcinomas resist PD-1-directed therapy. In a mouse model of pancreatic ductal adenocarcinoma (PDA), it has been shown that inhibiting the chemokine receptor, CXCR4, overcomes resistance to anti-PD-L1. Here, we show that the PDA cancer cells exhibit an extracellular, covalent complex between keratin 19 (KRT19) and CXCL12, the ligand for CXCR4, which is produced by the cancer-associated fibroblast (CAF). PDA tumors containing gene-edited cancer cells that cannot express KRT19 or transglutaminase-2 (TGM2) lack the CXCL12-coat, are infiltrated with T cells, and regress during treatment of tumor-bearing mice with anti-PD-1. Therefore, TGM2 of pancreatic cancer cells enables their escape from immune attack by capturing the immune suppressive chemokine of the CAF. These findings may explain the resistance to immunotherapy of multiple human adenocarcinomas in which we find this CXCL12-coat.