Abstract 5923: Developing a novel system for studying tumor microenvironment heterogeneity in pancreatic adenocarcinoma

Abstract

Abstract Pancreatic cancer (PDA) has a dismal prognosis and responds poorly to all existing therapies. This is largely attributed to the existence of dense stroma and lack of T cell infiltration. PDA exhibits heterogeneous tumor microenvironments that are composed of various stromal cells. Human PDA has been shown to have various levels of T cell infiltration. The mechanisms underlying the inter-tumor heterogeneity of immune microenvironment in PDA and its effects on distinct responses of PDA to therapies, especially immune-modulating therapies, remain largely unknown. Our lab has demonstrated that there is no difference in somatic mutation burden or neo-epitope load between human PDA tumors with high or low amount of cytolytic T cells. We hypothesize that tumor-cell-intrinsic determinants, transcriptional and/or epigenetic factors, shape the heterogenous tumor immune microenvironment, and thereby result in different responses to therapies. For the reason that tumor cellularity of PDA is very low, the profiling of bulk tumor samples cannot provide enough information for understanding tumor-cell-intrinsic molecular events associated with differential immune microenvironment. Therefore, we developed a panel of ~60 cell lines (diversity-cell-panel) from PDA tumors derived from inbred C57BL/6 KPC mouse model, which recapitulates the major histopathological and molecular features of human PDA. Our preliminary results have demonstrated that the diversity-cell-panel recapitulates the immune microenvironments heterogeneity in PDA. Tumor cells mainly fell into two subgroups: T-cell-high and T-cell-low. Tumors resulted from T-cell-high tumor cells also possess less amount of immune-suppressive myeloid cells. To study whether this difference is caused by various amount of mutations, we performed exome-sequencing for 8 cell lines within this cell-panel, and showed that T cell-high and T-cell-low tumor cells have similar amount of mutations and neo-epitopes. To further study the distinct molecular features of T-cell-high and T-cell-low tumor cells, we will perform RNA-seq and ATAC-seq on tumor cells sorted from resulting tumors. To understand whether T cell infiltration affects the response of PDA tumors to immune-modulating therapies, I have been testing the response of T-cell-high and T-cell-low tumors to a group of therapies, including chemotherapy, CD40 therapy and immune checkpoint blockade therapy. Utilizing this novel system, the cell-panel, this study will delineate in unprecedented detail the novel molecular determinants of immune heterogeneity in PDA and the implication of the heterogeneity to therapies. This diversity-cell-panel will also be useful for understanding other aspects of tumor heterogeneity, including angiogenesis, drug resistance and metastatic disease. Citation Format: Jinyang Li. Developing a novel system for studying tumor microenvironment heterogeneity in pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5923. doi:10.1158/1538-7445.AM2017-5923