Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms
Abstract
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.
Article Details
Authors (37)
Shivan Sivakumar
Department of Immunology and Immunotherapy, School of Infection, Inflammation, and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom
Ashwin Jainarayanan
Edward Arbe-Barnes
Piyush Kumar Sharma
Maire Ni Leathlobhair
Sakina Amin
David J. Reiss
Lara Heij
Samarth Hegde
Assaf Magen
Felicia Tucci
Bo Sun
Shihong Wu
Nithishwer Mouroug Anand
Hubert Slawinski
Santiago Revale
Isar Nassiri
Jonathon Webber
Gerard D. Hoeltzel
Adam E. Frampton
Oncology Section, Surrey Cancer Research Institute, Department of Clinical and Experimental Medicine, FHMS, University of Surrey, The Leggett Building, Daphne Jackson Road, Guildford GU2 7WG, U.K.
Georg Wiltberger
Ulf Neumann
Philip Charlton
Laura Spiers
Tim Elliott
Maria Wang
Suzana Couto
Genmab US, Inc., Building 2, 777 Scudders Mill Rd, Princeton, New Jersey 08540, United States
Thomas Lila
Pallavur V. Sivakumar
Alexander V. Ratushny
Mark R. Middleton
Dimitra Peppa
Benjamin Fairfax
Miriam Merad
Michael L. Dustin
Enas Abu-Shah
Rachael Bashford-Rogers