Genomic copy-number variants drive apoptotic evasion underlying acquired resistance to immune checkpoint inhibitors
Patients who initially respond to immune checkpoint inhibitors (ICIs) often relapse. Here, we studied how disease-progressive (DP) clinical melanomas evolve genomically to acquire ICI resistance. Compared to patient-matched pretreatment tumors, DP tumors recurrently amplified and/or deleted anti-apoptotic and/or pro-apoptotic genes, respectively. By chronic exposure to killer T cells or ICI therapy, we derived acquired-resistant (AR) human melanoma cell lines and murine melanoma tumors that recapitulate co-occurrent copy-number variants (CNVs) of apoptotic genes observed in DP melanomas. AR and DP subclones expanded shared, private, and, in some subclones, preexistent driver CNVs. Compared to isogenic parental cells, AR melanoma cells attenuated apoptotic priming but, with overexpression of deleted pro-apoptotic genes, recovered mitochondrial priming and sensitivity to killer T cells or ICIs. In mice, pharmacologically reducing the apoptotic threshold of ICI persisters prevented relapses. Thus, CNVs can drive the evolution of resistance to ICIs in melanoma, with tumor cell-intrinsic apoptotic threshold representing a target to curtail persister evolution.
Authors
- Jianfeng Fan
- Mehdi Nosrati (ORCID: https://orcid.org/0000-0002-0114-5864)
- Alessio Giubellino (ORCID: https://orcid.org/0000-0002-5352-0662)
- Kevin B. Kim (ORCID: https://orcid.org/0000-0003-0694-0530)
- Shirley H. Lomeli (ORCID: https://orcid.org/0000-0002-0872-8309)
- Sixue Liu (ORCID: https://orcid.org/0000-0003-0323-4104)
- Mark C. Kelley (ORCID: https://orcid.org/0000-0002-5188-1931)
- Roger S. Lo (ORCID: https://orcid.org/0000-0002-5337-5004)
- Douglas Buckner Johnson (ORCID: https://orcid.org/0000-0002-6390-773X)
- Gatien Moriceau (ORCID: https://orcid.org/0000-0003-3904-7669)
- Shangfeng Yang (ORCID: https://orcid.org/0000-0002-6931-9613)
- Zhentao Yang (ORCID: https://orcid.org/0000-0003-3563-8912)
- Mohammed Kashani–Sabet (ORCID: https://orcid.org/0000-0001-5265-0011)
- Mingming Wu (ORCID: https://orcid.org/0000-0001-8420-3750)
- Prashanthi Dharanipragada (ORCID: https://orcid.org/0000-0002-1808-237X)
- Carlos Prieto‐Granada (ORCID: https://orcid.org/0000-0002-5025-7539)
- Robert Damoiseaux
Institutions
- University of Minnesota (US)
- University of California, Los Angeles (US)
- California Pacific Medical Center (US)
- University of Minnesota Medical Center (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Immunity
- Published
- 2025-10-31
- DOI
- https://doi.org/10.1016/j.immuni.2025.10.001
- Citations
- 2
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.61