Abstract IA11: T cell exclusion in pancreatic ductal adenocarcinoma: The FAP+ cancer-associated fibroblast and CXCL12

Abstract

Abstract Patients with pancreatic adenocarcinoma (PDA), unlike those with melanoma, non-small cell lung cancer and renal cell carcinoma, did not have objective responses to the T cell checkpoint antagonists, antibodies to CTLA-4 and PD-L1, that promote the anti-cancer function of T cells. We sought the basis for this phenomenon by examining the interaction between the immune system and PDA in a genetically engineered mouse model of this disease, the KrasLSL.G12D/+; p53R172H/+; PdxCreTg/+ (or KPC) model. PDA in KPC mice, as in human patients, is resistant to therapy with anti-CTLA-4 and anti-PD-L1, respectively. The explanation for this resistance of the PDA to immune therapy was shown not to be the absence of an anti-cancer cell adaptive immune response, but to be the exclusion of T cells from the vicinity of cancer cells within tumors. The exclusion was caused by the chemokine, CXCL12, that was produced by the carcinoma-associated fibroblasts that were identified by their expression of the membrane protein, FAP. Remarkably, CXCL12 was physically associated with the cancer cells, which were not producing the chemokine. Inhibiting the interaction of this CXCL12 with its receptor, CXCR4, on T cells by administering the drug, AMD3100, caused the rapid accumulation of T cells amongst cancer cells, uncovered the efficacy of anti-PD-L1, and greatly diminished the numbers of cancer cells within the PDA tumors after 6 days of treatment. Thus, pharmacological targeting of the CXCR4-CXCL12 interaction overcomes the dominant immune suppressive mechanism of T cell exclusion in murine PDA. This finding may be relevant to therapy of human PDA, which also exhibits T cell exclusion, coating of cancer cells with CXCL12, and, as noted above, resistance to anti-PD-L1. Citation Format: Douglas T. Fearon, Arnaud Pommier, Michael Ludwig, David Tuveson. T cell exclusion in pancreatic ductal adenocarcinoma: The FAP+ cancer-associated fibroblast and CXCL12. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA11.