Abstract IA21: The basis of immune suppression in murine pancreatic ductal adenocarcinoma

Abstract

Abstract Immune therapy of human pancreatic ductal adenocarcinoma (PDAC) with the T cell checkpoint antagonists, anti-CTLA-4 and anti-PD-L1, has been unsuccessful. To determine the reason for this, we studied the KPC mouse model of autochthonous PDAC in which cancer cells express KrasG12D and p53R172H, and have lost the wild type p53 allele (LOH). These tumors resemble human PDAC in not responding to treatment with anti-CTLA-4 or anti-PD-L1. PDAC-bearing mice have CD8+ T cells specific for antigen(s) expressed by cancer cells. Thus, the ineffectiveness of T cell checkpoint antagonist immune therapy is not explained by the absence of an anti-tumor immune response, and immune suppression in the tumor microenvironment must occur mainly by another means. We have shown that this immune suppressive process depends on the stromal cell known as the “cancer-associated fibroblast” (CAF) that is identified by the membrane protein marker, “fibroblast activation protein” (FAP). Conditionally depleting the FAP+ CAF (Kraman M, et al., Science 2010) leads to T cell-mediated slowing of PDAC growth, and co-treatment with anti-PD-L1 enhances this effect (Feig C, et al. PNAS 2013). Three observations directed attention to the chemokine, CXCL12, as the mediator of immune suppression: the FAP+ CAF is the source of CXCL12 mRNA in PDACs; CXCL12 protein selectively “coats” the cancer cells; and T cells are excluded from the CXCL12-coated cancer cell-containing regions of the tumor. We treated PDAC-bearing mice for 24 hr with AMD3100/Plerixafor, a small molecule antagonist of the CXCL12 receptor, CXCR4, alone or together with anti-PD-L1. Tumors from AMD3100-treated mice exhibit frequent T cells within cancer cell-containing regions, and tumors from dual treated mice have even more T cells. Importantly, whereas tumor volume doubles in control mice in 6 days, AMD3100 alone arrests tumor growth, and AMD3100 + anti-PD-L1 treatment decreases tumor volume by 15%. Both therapies eliminate almost all cancer cells, leaving a residual mass containing only PanIN, inflammatory cells, and desmoplastic matrix. These findings may be relevant not only to human PDAC, but also to colorectal and ovarian carcinoma, all of which also contain FAP+ CAFs and CXCL12-coated cancer cells, demonstrate exclusion of T cells from the vicinity of cancer cells, and are resistant to therapy with anti-PD-1/anti-PD-L1. Citation Format: Douglas T. Fearon. The basis of immune suppression in murine pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA21.