Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms
Shivan Sivakumar, Ashwin Jainarayanan, Edward Arbe-Barnes, Piyush Kumar Sharma, Máire Ní Leathlobhair, Sakina Amin, David J. Reiss, Lara R. Heij, Samarth Hegde, Assaf Magen, Felicia Anna Tucci, Bo Sun, Shihong Wu, Nithishwer Mouroug Anand, Hubert Slawinski, Santiago Revale, Isar Nassiri, Jonathon Webber, Gerard D. Hoeltzel, Adam E. Frampton, Georg Wiltberger, Ulf P. Neumann, Philip Charlton, Laura Spiers, Tim Elliott, Maria Wang, Suzana S. Couto, Thomas Lila, Pallavur V. Sivakumar, Alexander V. Ratushny, Mark R. Middleton, Dimitra Peppa, Benjamin P. Fairfax, Miriam Mérad, Michael L. Dustin, Enas Abu‐Shah, Rachael Bashford-Rogers
Abstract
Pancreatic ductal adenocarcinoma has a dismal prognosis. A comprehensive analysis of single-cell multi-omic data from matched tumour-infiltrated CD45+ cells and peripheral blood in 12 patients, and two published datasets, reveals a complex immune infiltrate. Patients have either a myeloid-enriched or adaptive-enriched tumour microenvironment. Adaptive immune cell-enriched is intrinsically linked with highly distinct B and T cell clonal selection, diversification, and differentiation. Using TCR data, we see the largest clonal expansions in CD8 effector memory, senescent cells, and highly activated regulatory T cells which are induced within the tumour from naïve cells. We identify pathways that potentially lead to a suppressive microenvironment, including investigational targets TIGIT/PVR and SIRPA/CD47. Analysis of patients from the APACT clinical trial shows that myeloid enrichment had a shorter overall survival compared to those with adaptive cell enrichment. Strategies for rationale therapeutic development in this disease include boosting of B cell responses, targeting immunosuppressive macrophages, and specific Treg cell depletion approaches.