Damle and Carter et al. integrated spatial proteomics, tissue microarray, multiplex immunofluorescence imaging, and transcriptomics data from highly desmoplastic fibrolamellar carcinoma, and identified DC:Th:CTL three-cell-type clusters were present non-randomly in the TME. Immune triads were enriched for cDC1, mregDC, CXCL13+ Th, and GZMK+ effector CTL cells, showed upregulation of immune activation markers, and were present in treatment-naive murine and human PDAC. The density of APC:Th:CTL three-cell-type clusters in primary PDAC samples (n=467) correlated with intratumoral clonal T cell expansion and improved OS.
Contributed by Shishir Pant
ABSTRACT: 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 colocalization of dendritic cells (DCs), helper T cells (Th), and cytotoxic T lymphocytes (CTL) within the tumor immune microenvironment following immune checkpoint blockade correlates with clinical response. Herein, we report the integration of more than one 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-nave and highly desmoplastic tumors, such as fibrolamellar carcinoma and pancreatic ductal adenocarcinoma (PDAC). We found that these immune triads were enriched for functionally important type 1 conventional DC, mature DCs enriched in immunoregulatory molecules (mregDC), CXCL13+ Th, and GZMK+ effector CTL phenotypes. Subsequent multiplex immunofluorescence imaging of more than 450 primary PDAC tumors showed that the density of antigen-presenting cell (APC):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.
Author Info: (1) University of Washington, Seattle, WA, United States. (2) University of Washington, United States. (3) University of Washington, United States. (4) University of Washington, Se
Author Info: (1) University of Washington, Seattle, WA, United States. (2) University of Washington, United States. (3) University of Washington, United States. (4) University of Washington, Seattle, WA, United States. (5) University of Washington, Seattle, United States. (6) University of Washington, Seattle, Washington, United States. (7) Washington University in St. Louis, Saint Louis, MO, United States. (8) Washington University in St. Louis, Saint Louis, MO, United States. (9) University of Washington, Seattle, WA, United States. (10) University of Washington, Seattle, United States. (11) University of Washington, United States. (12) University of Washington, WA, United States. (13) Fred Hutchinson Cancer Center, Seattle, WA, United States. (14) Fred Hutchinson Cancer Center, Seattle, WA, United States. (15) Washington University in St. Louis, United States. (16) Washington University in St. Louis, St. Louis, MO, United States. (17) University of Washington, Seattle, WA, United States. (18) University of Washington, Seattle, WA, United States. (19) University of California, San Francisco, San Francisco, CA, United States. (20) Washington University in St. Louis, St. Louis, MO, United States. (21) University of Washington, Seattle, United States. (22) University of Washington, Seattle, WA, United States.
