Abstract A20: Gemcitabine primes the pancreatic tumor microenvironment for second-line immunotherapy

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6-12 months. As most patients present with disseminated disease, the majority are offered palliative chemotherapy. As there are no treatment strategies for patients who progress on chemotherapy, we explored the effects of long-term gemcitabine on the tumor microenvironment in order to identify potential therapeutic options in chemorefractory PDAC. Using a combination of mouse models and human-derived PDAC cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high-throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, gemcitabine led to large-scale alterations in the tumor secretome, namely by increasing the synthesis of CCL/CXCL chemokines and TGFβ-associated proteins. These secreted factors altered the composition of the tumor stroma, conferring drug resistance to cancer-associated fibroblasts in vitro. We therefore combined gemcitabine with anti-PD-1 in transgenic models of murine PDAC, which failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signal deficiency, gemcitabine and anti-PD-1 led to a robust CD8+ T cell-response and decrease in tumor burden. These results suggest that gemcitabine may prime PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation, but requires the inhibition of a TGFβ cytokine barrier. Given the current lack of third-line treatment options, this approach warrants consideration in the management of gemcitabine-refractory PDAC. Citation Format: Daniel R. Principe, Matthew Narbutis, Sandeep Kumar, Alex Park, Navin Viswakarma, Matthew J. Dorman, Suneel D. Kamath, Hidayatullah G. Munshi, Ajay Rana. Gemcitabine primes the pancreatic tumor microenvironment for second-line immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A20.