Tumor cell heterogeneity drives spatial organization of the intratumoral immune response
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.
Authors
- Oscar A. Aguilar (ORCID: https://orcid.org/0000-0002-7990-8745)
- Savannah Hughes (ORCID: https://orcid.org/0009-0007-3593-6756)
- Cecilia Ledezma-Soto
- Kelly Kersten (ORCID: https://orcid.org/0000-0001-7615-2594)
- Melissa Quino Reeves (ORCID: https://orcid.org/0000-0002-4886-5164)
- Matthew F. Krummel (ORCID: https://orcid.org/0000-0001-7915-3533)
- Kenneth Ng
- Kenneth H. Hu (ORCID: https://orcid.org/0000-0002-0294-0202)
- Bushra Samad (ORCID: https://orcid.org/0000-0002-2893-0897)
- Piyush Chaudhary
- Lotus Lum (ORCID: https://orcid.org/0000-0003-4751-0764)
- Daphne Superville (ORCID: https://orcid.org/0000-0002-8317-8431)
- Lawrence H. Fong (ORCID: https://orcid.org/0000-0002-6428-428X)
- Alexis J. Combes (ORCID: https://orcid.org/0000-0002-9110-6542)
- Arun K. Chumber (ORCID: https://orcid.org/0009-0004-8247-437X)
- Carmela Benson (ORCID: https://orcid.org/0000-0002-6258-7412)
- Miho Tanaka (ORCID: https://orcid.org/0000-0002-0905-9346)
- Zoe Adams
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- University of California, San Francisco (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of Utah (US)
- Discovery Institute (US)
- Huntsman Cancer Institute (US)
- Fred Hutch Cancer Center (US)
- Parker Institute for Cancer Immunotherapy (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-02-26
- DOI
- https://doi.org/10.1084/jem.20242282
- Citations
- 13
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 13.59
Funders
- American Cancer Society
- V Foundation for Cancer Research
- Cancer Prevention and Research Institute of Texas
- University of Texas System
- Cancer League of Colorado
- Huntsman Cancer Institute
- Parker Institute for Cancer Immunotherapy
- National Institutes of Health
- University of California, San Francisco
- National Cancer Institute