High Dimensional Profiling of T cells in latent infections and cancer
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, and more plasmocytes in circulation in pancreatic cancer patients compared to age-matched controls. Using high dimensional approaches, we observe skewed T cell differentiation in pancreatic cancer patients, with CD8 T cells biased towards more CD45RA-positive CD27-positive CCR7-positive CD95-positive CD49d-positive stem cell memory cells (P=3x10-4), 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=0.01) than age-matched controls. We further examinated alterations of T cell differentiation in CD8 T cell compartment in human spleens, and report increased proportions of late effector memory T cells in pancreatic cancer patients as compared to age-matched controls. Comparable observation of increased numbers of intra-splenic effector T cells was made in genetically engineered (KPC mice: LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre), as well as orthotopic mouse models of pancreatic cancer. In the former model, we observed an accumulation of adoptively transferred listeria-experienced effector T cells in the spleen. Together, these results demonstrate a trafficking defect of experienced T cells in the context of pancreatic cancer at baseline. We are now investigating the mechanisms underlying these observations, as well as their impact on T cell immunity of the patients. Our goal is to understand the nature of the skewing and how any changes in baseline immune health of the T cell compartment related to disease progression and/or response to therapy. These studies should provide a foundation for improving therapy in pancreatic cancer patients. Additionally, they should provide new insights into the heterogeneity of T cell differentiation.
Wherry lab, Institute for Immunology, Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA
Domain 3 - U932 - Immunity and Cancer