Abstract A123: Skewed CD4 and CD8 T-cell differentiation in pancreatic cancer patients

Abstract

To understand potential immune system alterations in newly diagnosed, untreated, pancreatic cancer patients and provide a foundation for immunotherapy, we profiled PBMC from pancreatic ductal adenocarcinoma (PDA) patients and age-matched healthy controls using high-dimensional CyTOF analysis. We developed two immune profiling panels: a broad profiling panel that includes 45 phenotypic markers that together permit the identification and enumeration of the main innate and adaptive immune cell subsets in humans, and a deep profiling panel that includes 45 features focusing on T-cell phenotype and biology. We report a 2-fold increase in monocytes, more regulatory T-cells, and more plasmocytes in circulation in pancreatic cancer patients as compared to age-matched controls, as well as a bias towards cytokine-producing NK cells. Using high-dimensional approaches, we observed skewed T-cell differentiation in pancreatic cancer patients, with peripheral blood CD8 T-cells being biased towards more CD45RA-positive CD27-positive CCR7-positive CD95-positive CD49d-positive stem cell memory cells (P=7x10-5), more CD45RA-negative CD27-positive CCR7-negative effector memory cells (P=0.002) and less CD45RA-positive CD27-negative CCR7-negative late effector memory cells (P=0.003) as compared to age-matched controls. Strikingly, when examinating T-cell differentiation in human spleens, we found increased proportions of late effector memory T-cells in the splenic CD8 T-cell compartment of pancreatic cancer patients as compared to age-matched controls. These results suggest an impaired T-cell trafficking in pancreatic cancer patients, with late memory T-cells being retained in the spleen. We are now investigating the mechanisms underlying these observations, as well as their impact on T-cell immunity of the cancer patients. Our goal is to understand the nature of the skewing and how any changes in baseline immune health of the T-cell compartment relate to disease progression and/or response to therapy. These studies should provide a foundation for improving therapy in pancreatic cancer patients. Citation Format: Cecile Alanio, Bertram Bengsch, Josephine R. Gies, Sarah Henrickson, Nan Ping Weng, Janae A Ritz-Romeo, Mark O9Hara, Joseph J Melenhorst, Simon Lacey, Regina M Young, Carl H June, E. John Wherry. Skewed CD4 and CD8 T-cell differentiation in pancreatic cancer patients [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 A123.