Abstract 1011: Tumor cell intrinsic factors dictate T cell infiltration and therapeutic response in pancreatic ductal adenocarcinoma
Authors: Byrne Katelyn T. , Li Jinyang , Vonderheide Robert H. , Stanger Ben Z. 
Published: August 2018

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, CD103+ dendritic cells (DCs), and a dearth of myeloid derived suppressor cells (MDSCs). In contrast, the remaining 10/17 tumor clones were categorized as ‘T cell low' lines, with TME dominated by myeloid cells and macrophages, especially granulocytic MDSCs. 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 and chemotherapy. 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 (62.9% vs. 50.2% IFN-g+ in T cell high vs low, p=0.06). 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&lt;0.0001), and predicted response to therapy across the panel of tumor clones. CD44hiPD-1+ CD8 T cells trafficked in to the tumor site independently of CXCR3 (53.8% in control vs. 50.0% in anti-CXCR3 treated tumors, p=0.8), in contrast to the bulk CD8 T cell population which required CXCR3 to enter the TME (7.5% in control vs 0.53% in anti-CXCR3 treated tumors, p&lt;0.01). Furthermore, in Batf3 KO mice, T cell high tumors lacked CD8 T cells and resembled T cell low tumors, indicating the requirement for CD103+ DCs in the TME for T cell infiltration. These data reveal tumor cell intrinsic factors as major determinants of immune heterogeneity in the TME, and highlight the use of this panel of clonal tumor lines as a tool to probe the immune heterogeneity of the TME. Future studies will identify the specific factors regulating T cell infiltration and mechanisms to convert T cell low tumors to T cell high tumors, thereby improving responses to immunotherapy.

Citation Format: Katelyn T. Byrne, Jinyang Li, Robert H. Vonderheide, Ben Z. Stanger. Tumor cell intrinsic factors dictate T cell infiltration and therapeutic response in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1011.