Genome-scale spatial mapping of the Hodgkin lymphoma microenvironment identifies tumor cell survival factors
A central challenge in cancer research is to identify the secreted factors that sustain tumor cell survival. This is best exemplified in Hodgkin lymphoma, where malignant cells constitute a minor fraction of the tumor and rely on signals from the microenvironment for survival. Using genome-wide transcriptional profiling with spatial and single-cell resolution, we show that the neighborhood around malignant cells forms a distinct niche of 31 non-malignant cell types, enriched in helper T cells and myeloid cells, but depleted of plasma cells. Moreover, our spatial analysis nominates IL13 as a candidate survival factor. Recombinant IL13 augments malignant cell growth in vitro, and genome-wide loss-of-function screens across >1000 human cancer cell lines identify IL4R and IL13RA1, heterodimeric components of the IL13 receptor, as uniquely essential in Hodgkin lymphoma. Importantly, blocking antibodies phenocopy genetic inactivation. Our findings provide a biological rationale for testing IL13-directed therapies, which are already FDA-approved, in Hodgkin lymphoma.
Authors
- Jackson A. Weir (ORCID: https://orcid.org/0000-0001-8741-1344)
- Caroline Uhler (ORCID: https://orcid.org/0000-0002-7008-0216)
- Margaret A. Shipp (ORCID: https://orcid.org/0000-0002-3949-6897)
- Orr Ashenberg (ORCID: https://orcid.org/0000-0002-7802-8834)
- Abner Louissaint (ORCID: https://orcid.org/0000-0001-6707-917X)
- Gail Newton
- Naeem Nadaf (ORCID: https://orcid.org/0000-0002-7805-8523)
- Neriman Tokcan (ORCID: https://orcid.org/0000-0001-7676-5534)
- Evan Z. Macosko (ORCID: https://orcid.org/0000-0002-2794-5165)
- Haley Martin
- Dylan Cable (ORCID: https://orcid.org/0000-0001-7042-2960)
- Daniel Chafamo (ORCID: https://orcid.org/0009-0001-8877-5913)
- Fei Chen (ORCID: https://orcid.org/0000-0003-2308-3649)
- Scott Rodig
- Seán M. Sullivan (ORCID: https://orcid.org/0000-0002-7393-263X)
- Mehdi Borji (ORCID: https://orcid.org/0009-0002-7023-434X)
- TR Golub
- Irving A. Barrera
- Geraldine Pinkus
- Vignesh Shanmugam
- Saoirse Hanbury
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Michigan (US)
- University of Massachusetts Boston (US)
- University of Chicago (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Decision Systems (United States) (US)
- Massachusetts Institute of Technology (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-20
- DOI
- https://doi.org/10.1038/s41467-025-67539-1
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00