CRATER tumor niches facilitate CD8+ T cell engagement and correspond with immunotherapy success
T cell-mediated tumor killing underlies immunotherapy success. Here, we used long-term in vivo imaging and high-resolution spatial transcriptomics of zebrafish endogenous melanoma, as well as multiplex imaging of human melanoma, to identify domains facilitating the immune response during immunotherapy. We identified cancer regions of antigen presentation and T cell engagement and retention (CRATERs) as pockets at the stroma-melanocyte boundaries of zebrafish and human melanoma. CRATERs are rich in antigen-recognition molecules, harboring the highest density of CD8<sup>+</sup> T cells in tumors. In zebrafish, CD8<sup>+</sup> T cells formed prolonged interactions with melanoma cells within CRATERs, characteristic of antigen recognition. Following immunostimulatory treatment, CRATERs expanded, becoming the major sites of activated CD8<sup>+</sup> T cell accumulation and tumor killing. In humans, elevation in CRATER density in biopsies following immune checkpoint blockade (ICB) therapy correlated with a clinical response to therapy. CRATERs are structures that show active tumor killing and may be useful as a diagnostic indicator for immunotherapy success.
Authors
- Aditi Sahu (ORCID: https://orcid.org/0000-0003-0004-3839)
- Hannah L. Cole (ORCID: https://orcid.org/0000-0002-3023-8998)
- Song Yang (ORCID: https://orcid.org/0000-0002-3064-3141)
- Cecília Pessoa Rodrigues (ORCID: https://orcid.org/0000-0001-8617-6565)
- Milind Rajadhyaksha (ORCID: https://orcid.org/0000-0002-6323-4547)
- Sophia Liu (ORCID: https://orcid.org/0000-0003-3614-9731)
- Irving Barrera (ORCID: https://orcid.org/0000-0001-6099-4316)
- David P. Hoytema van Konijnenburg (ORCID: https://orcid.org/0000-0001-5198-9718)
- Gëorge F. Murphy (ORCID: https://orcid.org/0000-0001-9362-5146)
- Douglas S. Richardson (ORCID: https://orcid.org/0000-0002-3189-2190)
- Emily Formato (ORCID: https://orcid.org/0000-0001-5891-2561)
- James E. Sefton
- Biagio Ricciuti (ORCID: https://orcid.org/0000-0002-0651-2678)
- Kai W. Wucherpfennig (ORCID: https://orcid.org/0000-0002-1829-302X)
- Hadley M. Moreau
- N. Besson (ORCID: https://orcid.org/0009-0008-3548-913X)
- W Mccall
- Aya Ludin
- Liang Deng (ORCID: https://orcid.org/0000-0002-8467-9342)
- Scott J. Rodig (ORCID: https://orcid.org/0000-0003-1761-9769)
- Peter Karl Sorger (ORCID: https://orcid.org/0000-0002-3364-1838)
- Meredith E. Stanhope (ORCID: https://orcid.org/0000-0002-6358-4141)
- Elizabeth R. Jerison (ORCID: https://orcid.org/0000-0003-3793-8839)
- Michael P. Manos (ORCID: https://orcid.org/0000-0003-0841-207X)
- Miguel Córdova (ORCID: https://orcid.org/0000-0002-2962-0671)
- Kathleen L. Pfaff (ORCID: https://orcid.org/0000-0003-3311-5384)
- Ajit J. Nirmal (ORCID: https://orcid.org/0000-0003-4139-0618)
- Joao V. Alessi (ORCID: https://orcid.org/0000-0002-8072-5946)
- Mark M. Awad (ORCID: https://orcid.org/0000-0003-0928-5244)
- Leonard Ira Zon (ORCID: https://orcid.org/0000-0003-0860-926X)
- Alexander B. Afeyan (ORCID: https://orcid.org/0000-0003-0525-7166)
- Georgia L. Stirtz
- Stephen R. Quake (ORCID: https://orcid.org/0000-0002-1613-0809)
- Fei Chen (ORCID: https://orcid.org/0000-0003-2308-3649)
- Yi Zhou (ORCID: https://orcid.org/0000-0001-5195-5294)
- Lijian Wu (ORCID: https://orcid.org/0000-0001-6318-380X)
- Stephanie M. Jones (ORCID: https://orcid.org/0000-0003-4697-3169)
- Jodi D. Weiss
- F. Stephen Hodi
- Qiyu Gong
- Billie Porter
- Asaf Tal
- Hannah Mae Faulkner
- Nebiyat Eskndir
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- University of Chicago (US)
- Dana-Farber Cancer Institute (US)
- Chan Zuckerberg Initiative (United States) (US)
- Center for Systems Biology (US)
- Harvard Stem Cell Institute (US)
- Dana-Farber Brigham Cancer Center (US)
Publication Details
- Journal
- Cell
- Published
- 2025-10-17
- DOI
- https://doi.org/10.1016/j.cell.2025.09.021
- Citations
- 4
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 4.18