Abstract 1686: Epigenetic modulation of the tumor microenvironment enhances vaccine induced T cell responses in a murine model of pancreatic cancer
Authors: Christmas Brian , Scott Blake , Armstrong Todd , Azad Nilofer , Jaffee Elizabeth 
Published: July 2017

This project aims to test the hypothesis that epigenetic modulatory drugs (EMD) and GVAX, a GM-CSF-secreting whole tumor cell vaccine, are capable of altering the inflammatory environment of pancreatic ductal adenocarcinoma (PDAC) and sensitizing it to checkpoint blocking agents.

Recently the use of antibody therapy targeting immune checkpoints, such as CTLA-4 and PD-1, has become a major focus of cancer immunotherapy. In responsive patients, these therapies have resulted in long-term control of chemotherapy-resistant disease. The most compelling activity has been seen in the minority of patients with immunogenic tumors where T cell infiltration naturally occurs. These benefits are not observed in non-immunogenic tumors, such as PDAC, with low expression of tumor-associated antigens (TAA) and a lack of intrinsic T cell infiltrates. Therapies that can alter the tumor microenvironment (TME) and allow infiltration of effector T cells, decrease immunosuppressive cells, and stimulate TAA expression may convert non-immunogenic tumors into cancers sensitive to checkpoint inhibitors. Recent work with EMDs has shown that they are capable of altering the immunogenicity of the TME by inducing the expression of cancer testis antigens as well as increasing tumor cell expression of MHC class II and decreasing Tregs in the TME. Additionally, GVAX has been shown to induce tertiary lymphoid aggregates within the TME of patients with PDAC.

We are testing the hypothesis that treatment with EMDs and GVAX can sensitize the inflammatory environment of PDAC to checkpoint blockade inhibition by evaluating changes in immune cell function within the TME via flow cytometry, immunohistochemistry, and gene expression array. We are using a murine model of hepatic metastases of pancreatic cancer which involves injecting syngeneic pancreatic tumor cells into the spleen followed by a hemisplenectomy, resulting in the consistent formation of hepatic metastases that can be monitored by ultrasound. We have evaluated entinostat, a histone deacetylase inhibitor, in combination with GVAX which induces T cell responses, and demonstrated a significant increase in survival when compared with either agent alone. Flow cytometric analysis of the cells infiltrating the TME shows that the combination of entinostat and GVAX causes a significant increase in CD4+ T cell infiltration as well as a shift from an M-MDSC dominant to a more G-MDSC dominant myeloid population. Current studies aim to elucidate the functionality of the MDSC population as well as identify potential changes in the T helper cell subsets via flow cytometry. Additionally, future studies will evaluate changes within checkpoint blockade pathways via flow cytometry and gene expression array to identify pathways that require further modulation to enhance antitumor responses.

Citation Format: Brian Christmas, Blake Scott, Todd Armstrong, Nilofer Azad, Elizabeth Jaffee. Epigenetic modulation of the tumor microenvironment enhances vaccine induced T cell responses in a murine model of pancreatic cancer [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 1686. doi:10.1158/1538-7445.AM2017-1686