Intratumoral Three-Cell-Type Clusters Are a Conserved Feature of Endogenous Antitumor Immunity
Effective antitumor immunity ultimately depends on the priming and activation of tumor-specific cytotoxic CD8+ T cells; however, the role of intratumoral cell-cell immune interactions remains incompletely understood. Recent work has revealed that the temporospatial co-localization of dendritic cells (DC), T helper (Th) cells, and cytotoxic T lymphocytes (CTL) within the tumor immune microenvironment following immune checkpoint blockade correlates with clinical response. In this study, we report the integration of more than 1 million spatially resolved single-cell profiles across six spatial proteomic and transcriptomic assays, which demonstrated that DC:Th:CTL three-cell-type clusters were common even in immunotherapy-naïve and highly desmoplastic tumors, such as fibrolamellar carcinoma and pancreatic ductal adenocarcinoma. We found that these immune triads were enriched for functionally important type 1 conventional DC, mature DCs enriched in immunoregulatory molecules, CXCL13+ Th, and GZMK+ effector CTL phenotypes. Subsequent multiplex immunofluorescence imaging of more than 450 primary pancreatic ductal adenocarcinoma tumors showed that the density of antigen-presenting cell:Th:CTL three-cell-type clusters was correlated with intratumoral T-cell clonal expansion and improved overall survival. These findings suggest that DC:Th:CTL triads are conserved across solid tumors and highlight the importance of intratumoral spatial niches in mediating endogenous antitumor immunity.
Authors
- Kiran Vij (ORCID: https://orcid.org/0000-0003-3633-0565)
- Marianna B. Ruzinova (ORCID: https://orcid.org/0000-0002-0833-8335)
- Jacqueline L. Mudd (ORCID: https://orcid.org/0000-0001-7618-8765)
- Ian Nicholas Crispe (ORCID: https://orcid.org/0000-0003-2375-5863)
- Kristin E. Goodsell (ORCID: https://orcid.org/0000-0002-5967-7433)
- Venu G. Pillarisetty (ORCID: https://orcid.org/0000-0002-1162-9643)
- Sujata Jana (ORCID: https://orcid.org/0000-0003-2718-0307)
- Eric A. Collisson (ORCID: https://orcid.org/0000-0001-8037-9388)
- Amanda Koehne (ORCID: https://orcid.org/0000-0002-1397-6964)
- X Jiang (ORCID: https://orcid.org/0009-0007-1470-0760)
- Jose Mario Bello Pineda (ORCID: https://orcid.org/0000-0003-1417-9200)
- Shreeram Akilesh (ORCID: https://orcid.org/0000-0003-3152-7991)
- Heidi L. Kenerson (ORCID: https://orcid.org/0000-0002-4497-4101)
- Emily Beirne (ORCID: https://orcid.org/0009-0008-3325-082X)
- Jack Cernak (ORCID: https://orcid.org/0009-0008-8191-7449)
- Raymond S. Yeung (ORCID: https://orcid.org/0000-0001-5090-3046)
- Thomas Walsh (ORCID: https://orcid.org/0009-0007-5435-2561)
- Ryan C. Fields (ORCID: https://orcid.org/0000-0001-6176-8943)
- Lindsay K. Dickerson (ORCID: https://orcid.org/0000-0001-6509-8393)
- Sheela Damle (ORCID: https://orcid.org/0000-0001-6688-0950)
- Jason A. Carter (ORCID: https://orcid.org/0009-0002-7397-0502)
- Sardar Shahmir B. Chauhan (ORCID: https://orcid.org/0009-0009-7421-067X)
Institutions
- University of California, San Francisco (US)
- University of Washington (US)
- Washington University in St. Louis (US)
- University of Rochester Medical Center (US)
- Fred Hutch Cancer Center (US)
- University of Washington Applied Physics Laboratory (US)
- Seattle University (US)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1158/2326-6066.cir-25-0062
- Citations
- 1
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.05