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<p>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.</p>

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Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月6日

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  • Shivan Sivakumar,
  • 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,
  • Georg Wiltberger,
  • Ulf Neumann,
  • Philip Charlton,
  • Laura Spiers,
  • Tim Elliott,
  • Maria Wang,
  • Suzana Couto,
  • 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

摘要

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.