Tumor cell heterogeneity drives spatial organization of the intratumoral immune response

作者：Miho Tanaka, Lotus Lum, Kenneth H. Hu, Piyush Chaudhary, Savannah Hughes, Cecilia Ledezma-Soto, Bushra Samad, Daphne Superville, Kenneth Ng, Arun K. Chumber, Ciara Benson, Zoe N. Adams, Kelly Kersten, Oscar A. Aguilar, Lawrence Fong, Alexis J. Combes, Matthew F. Krummel, Melissa Quino Reeves · 发表于：The Journal of Experimental Medicine · 年份：2025 · DOI：10.1084/jem.20242282 · 被引用次数：21 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Immune cells in cancer

Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. We modeled heterogeneous tumors comprised of "hot" and "cold" tumor populations (giving rise to T cell-rich and T cell-poor tumors, respectively) and introduced fluorescent labels to enable precise spatial tracking. We found the cold tumor cell population exerted a "dominant cold" effect in mixed tumors. Strikingly, spatial analysis revealed that the tumor cells themselves created distinct local microenvironments within heterogeneous tumors: regions occupied by cold tumor cells showed pronounced immunosuppression, harboring increased CD206Hi macrophages and diminished local T cell function. This inferior T cell activity in cold regions persisted even after immunotherapy and mechanistically was mediated by CX3CL1 produced by the cold tumor cells. An immune cold tumor population within a heterogeneous tumor thus impairs tumor immunity on both a tumor-wide and a highly localized spatial scale.