Type I conventional dendritic cells facilitate immunotherapy in pancreatic cancer

• 成果类型: Article
• 署名作者: Mahadevan, Krishnan K.; Dyevoich, Allison M.; Chen, Yang; Li, Bingrui; Sugimoto, Hikaru; Sockwell, Amari M.; McAndrews, Kathleen M.; Sthanam, Lakshmi Kavitha; Wang, Huamin; Shalapour, Shabnam; Watowich, Stephanie S.; Kalluri, Raghu
• 署名单位: University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Rice University; Baylor College of Medicine
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8349
• DOI: 10.1126/science.adh4567
• 发表日期: 2024-06-28
• 关键词: carcinoma-associated fibroblasts; oncogenic kras; t-cells; myeloid cells; regulatory t; inflammation; immunity; blockade; therapy; pd-1

摘要

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8(+) T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8(+) T cells with potential therapeutic importance. This study identifies a fundamental difference in the immune microenvironment in PDAC concurrent with, or without, pancreatitis and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.