TY - JOUR
T1 - Intratumoral Three-Cell-Type Clusters Are a Conserved Feature of Endogenous Antitumor Immunity
AU - Damle, Sheela R.
AU - Carter, Jason A.
AU - Goodsell, Kristin E.
AU - Pineda, Jose M.B.
AU - Dickerson, Lindsay K.
AU - Jiang, Xiuyun
AU - Mudd, Jacqueline L.
AU - Walsh, Thomas
AU - Kenerson, Heidi L.
AU - Cernak, Jack
AU - Chauhan, Sardar Shahmir B.
AU - Beirne, Emily
AU - Jana, Sujata
AU - Koehne, Amanda L.
AU - Vij, Kiran R.
AU - Ruzinova, Marianna B.
AU - Yeung, Raymond
AU - Akilesh, Shreeram
AU - Collisson, Eric A.
AU - Fields, Ryan C.
AU - Crispe, I. Nicholas
AU - Pillarisetty, Venu G.
N1 - Publisher Copyright:
©2025 American Association for Cancer Research.
PY - 2026/2/1
Y1 - 2026/2/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105029413186
U2 - 10.1158/2326-6066.CIR-25-0062
DO - 10.1158/2326-6066.CIR-25-0062
M3 - Article
C2 - 41201469
AN - SCOPUS:105029413186
SN - 2326-6066
VL - 14
SP - 205
EP - 218
JO - Cancer immunology research
JF - Cancer immunology research
IS - 2
ER -