Abstract A054: Tumor cell intrinsic factors dictate immune cell infiltration and response to immunotherapy

Abstract

The establishment of immune heterogeneity in the tumor microenvironment (TME) is poorly understood, despite recent data that the success of immunotherapies is dictated by the immune environment of the tumor site. Pancreatic ductal adenocarcinoma (PDA) is characteristically devoid of CD8 T-cells and resistant to therapeutic intervention. However, a small subset of patients (15%) have tumors highly infiltrated by CD8 T-cells, correlating with improved overall survival. To better elucidate the determinants of immune heterogeneity in the PDA TME, we generated clones from spontaneous tumors harvested from KrasG12D+/-;Trp53R172H+/-;Pdx-1 Cre (KPC) mice, a genetically engineered mouse model of PDA. Using a panel of 17 tumor clones, we found the clones segregated in to two groups with differential immune cell infiltration upon implantation in congenic C57BL/6 mice. 7/17 tumor clones were categorized as “T-cell high,” with an immune infiltrate comprising CD8 T-cells and CD103+ dendritic cells (DCs). In contrast, the remaining 10 tumor clones were categorized as “T-cell low” lines, with the TME dominated by myeloid cells and macrophages, especially granulocytic myeloid-derived suppressor cells. Hypothesizing that increased T-cell infiltrate would render PDA sensitive to therapy, we treated two T-cell high and two T-cell low tumor clones with combination immunotherapy. Mice bearing T-cell high clones responded to therapy (7/7 and 4/7 mice cured) and formed protective memory responses against secondary tumor challenge, while none of the mice bearing T-cell low tumors responded to treatment (0/7 and 0/7 mice cured). At baseline, T-cell high tumors had similar proportions of functional CD8 T-cells as in T-cell low tumors. However, the proportion of activated CD44hiPD-1+ CD8 T-cells was significantly increased in T-cell high tumors (62.2% vs. 35.1% in T-cell low clones, p Citation Format: Katelyn T. Byrne, Jinyang Li, Robert H. Vonderheide, Ben Stanger. Tumor cell intrinsic factors dictate immune cell infiltration and response to immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A054.