Genomic mediators of acquired resistance to immunotherapy in metastatic melanoma
Although some patients with metastatic melanoma experience durable responses to immune checkpoint inhibitors (ICIs), most exhibit intrinsic or acquired resistance to these therapies. Here, we compare somatic genomic profiles from matched pre-treatment and post-resistance tumor biopsies in patients (n = 25) with metastatic melanoma who exhibited heterogeneous ICI responses to nominate additional mediators of acquired resistance. We find that several acquired resistance tumors exhibit defects in B2M or JAK1/2, consistent with prior findings. We also discover resistance-associated mutations in SEC24C and SEC24D in 3 patients. SEC24 has an essential role in the trafficking of the dsDNA sensor STING and has been linked to interferonopathies. Melanoma cells engineered to express the SEC24C mutations observed in patients exhibit diminished STING signaling, including decreased type I interferon production, antigen presentation, and a reduced capacity to activate cytotoxic T cells. This study nominates a role for aberrant STING trafficking in acquired resistance to ICIs.
Authors
- Hugo Sax (ORCID: https://orcid.org/0000-0002-1532-2198)
- Giacomo Oliveira (ORCID: https://orcid.org/0000-0001-7435-5603)
- Mouadh Benamar
- Douglas Buckner Johnson (ORCID: https://orcid.org/0000-0002-6390-773X)
- Julia Schiantarelli (ORCID: https://orcid.org/0000-0001-5705-1309)
- Eliezer M. Van Allen (ORCID: https://orcid.org/0000-0002-0201-4444)
- Catherine J. Wu (ORCID: https://orcid.org/0000-0002-3348-5054)
- Katie M. Campbell
- Scott J. Rodig (ORCID: https://orcid.org/0000-0003-1761-9769)
- Alice Bosma-Moody
- Antoni Ribas (ORCID: https://orcid.org/0000-0003-3669-8458)
- F. Stephen Hodi (ORCID: https://orcid.org/0000-0001-6825-091X)
- Rizwan Haq (ORCID: https://orcid.org/0000-0002-1290-9276)
- Jihye Park (ORCID: https://orcid.org/0000-0002-4451-2046)
- David Liu (ORCID: https://orcid.org/0000-0003-0346-5033)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of California, Los Angeles (US)
- Parker Institute for Cancer Immunotherapy (US)
- Dana-Farber Cancer Institute (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.ccell.2025.01.009
- Citations
- 25
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 19.94
Funders
- Pfizer
- AstraZeneca
- Melanoma Research Alliance
- Dana-Farber Cancer Institute
- Parker Institute for Cancer Immunotherapy
- Mark Foundation For Cancer Research
- Incyte
- National Institutes of Health
- Genentech
- Novartis Institutes for BioMedical Research