2. Academic Validation
  3. Genomic copy-number variants drive apoptotic evasion underlying acquired resistance to immune checkpoint inhibitors

Genomic copy-number variants drive apoptotic evasion underlying acquired resistance to immune checkpoint inhibitors

  • Immunity. 2025 Nov 11;58(11):2864-2877.e9. doi: 10.1016/j.immuni.2025.10.001.
Mingming Wu 1,  Shiyue Yang 1,  Zhentao Yang 1,  Jian Fan 1,  Shirley H Lomeli 1,  Prashanthi Dharanipragada 1,  Gatien Moriceau 1,  Robert Damoiseaux 2,  Mark C Kelley 3,  Carlos N Prieto-Granada 4,  Alessio Giubellino 5,  Mehdi Nosrati 6,  Mohammed Kashani-Sabet 6,  Kevin B Kim 6,  Douglas B Johnson 7,  Sixue Liu 1,  Roger S Lo 8
Affiliations

Affiliations

  • 1 Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 2 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • 3 Department of General Surgery, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 4 Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 5 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • 6 Center for Melanoma Research and Treatment, California Pacific Medical Center, San Francisco, CA, USA; California Pacific Medical Center Research Institute, San Francisco, CA, USA.
  • 7 Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 8 Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: [email protected].
PMID: 41175874 DOI: 10.1016/j.immuni.2025.10.001
Abstract

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.

Keywords

T cell cytotoxicity; acquired resistance; anti-CTLA-4; anti-PD-1; apoptosis sensitivity; copy-number variation; genomic evolution; immune checkpoint inhibitor; immune evasion; melanoma; single-cell whole-genome sequencing; whole-exome sequencing.

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