We investigate how myeloid subsets differentially shape immunity to pancreatic ductal adenocarcinoma (PDA). We show that tumor antigenicity sculpts myeloid cell composition and functionality. Antigenicity promotes accumulation of type 1 dendritic cells (cDC1), which is driven by Xcr1 signaling, and overcomes macrophage-mediated suppression. The therapeutic activity of adoptive T cell therapy or programmed cell death ligand 1 blockade required cDC1s, which sustained splenic Klrg1+ cytotoxic antitumor T cells and functional intratumoral T cells. KLRG1 and cDC1 genes correlated in human tumors, and PDA patients with high intratumoral KLRG1 survived longer than patients with low intratumoral KLRG1. The immunotherapy CD40 agonist also required host cDC1s for maximal therapeutic benefit. However, CD40 agonist exhibited partial therapeutic benefit in cDC1-deficient hosts and resulted in priming of tumorspecific yet atypical CD8+ T cells with a regulatory phenotype and that failed to participate in tumor control. Monocyte/macrophage depletion using clodronate liposomes abrogated T cell priming yet enhanced the antitumor activity of CD40 agonist in cDC1-deficient hosts via engagement of innate immunity. In sum, our study supports that cDC1s are essential for sustaining effective antitumor T cells and supports differential roles for cDC1s and monocytes/macrophages in instructing T cell fate and immunotherapy response.
Bibliographical noteFunding Information:
We thank Danielle Huggins, Kaylee Schwertfeger, and Jesse Williams and for providing expertise on the in vivo use of clodronate liposomes. We acknowledge the University of Minnesota Imaging Core for assistance with IVIS imaging and quantification. We acknowledge the University of Minnesota Flow Cytometry Resource for technical assistance and the University of Minnesota Research Animal Resource staff for animal husbandry and veterinary services. ALB is supported by a computational training award from the American Association of Immunologists. MRR is supported by NIH T32 AI 007313 and Dennis W. Watson Fellowship. EJS is supported by NIH T35 AI118620 and the Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship. IMS is supported by NIH R01 CA249393 and R01 CA255039, Department of Defense PA200286, American Association for Cancer Research Pancreatic Cancer Action Network Career Development Awards (17-20-25-STRO and 19-35-STRO), American Cancer Society Institutional Research Grant (124166-IRG-58-001-55-IRG65), and Randy Shaver Cancer and Community Fund. IMS is also supported by pilot awards from the Masonic Cancer Center and Cancer Research Translational Initiative (University of Minnesota Medical School).
© 2022, Burrack et al.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't