TY - JOUR
T1 - Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms
AU - Sivakumar, Shivan
AU - Jainarayanan, Ashwin
AU - Arbe-Barnes, Edward
AU - Sharma, Piyush Kumar
AU - Leathlobhair, Maire Ni
AU - Amin, Sakina
AU - Reiss, David J.
AU - Heij, Lara
AU - Hegde, Samarth
AU - Magen, Assaf
AU - Tucci, Felicia
AU - Sun, Bo
AU - Wu, Shihong
AU - Anand, Nithishwer Mouroug
AU - Slawinski, Hubert
AU - Revale, Santiago
AU - Nassiri, Isar
AU - Webber, Jonathon
AU - Hoeltzel, Gerard D.
AU - Frampton, Adam E.
AU - Wiltberger, Georg
AU - Neumann, Ulf
AU - Charlton, Philip
AU - Spiers, Laura
AU - Elliott, Tim
AU - Wang, Maria
AU - Couto, Suzana
AU - Lila, Thomas
AU - Sivakumar, Pallavur V.
AU - Ratushny, Alexander V.
AU - Middleton, Mark R.
AU - Peppa, Dimitra
AU - Fairfax, Benjamin
AU - Merad, Miriam
AU - Dustin, Michael L.
AU - Abu-Shah, Enas
AU - Bashford-Rogers, Rachael
PY - 2025/2/6
Y1 - 2025/2/6
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-024-55424-2
DO - 10.1038/s41467-024-55424-2
M3 - Article
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1397
ER -