Type I Conventional Dendritic Cells Facilitate Immunotherapy in Pancreatic Cancer

Authors

Krishnan K Mahadevan
Allison M Dyevoich
Yang Chen
Bingrui Li
Hikaru Sugimoto
Amari M Sockwell
Kathleen M McAndrews
Lakshmi Kavitha Sthanam
Huamin Wang
Shabnam Shalapour
Stephanie S Watowich
Raghu Kalluri

Publication Date

6-28-2024

Journal

Science

Abstract

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.

Keywords

Animals, Mice, Cancer Vaccines, Carcinoma, Pancreatic Ductal, CD8-Positive T-Lymphocytes, Dendritic Cells, Immune Checkpoint Inhibitors, Immunotherapy, Mice, Inbred C57BL, Pancreatic Neoplasms, Pancreatitis, Tumor Microenvironment

DOI

10.1126/science.adh4567

PMID

38935717

PMCID

PMC11841451

PubMedCentral® Posted Date

2-20-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes