2025-11-04 カリフォルニア大学ロサンゼルス校(UCLA)
Web要約 の発言:
<関連情報>
- https://newsroom.ucla.edu/stories/how-melanoma-skin-cancer-evolves-to-resist-immunotherapy
- https://www.cell.com/immunity/fulltext/S1074-7613(25)00431-5
ゲノムコピー数変異は免疫チェックポイント阻害剤に対する獲得耐性の根底にあるアポトーシス回避を促進する Genomic copy-number variants drive apoptotic evasion underlying acquired resistance to immune checkpoint inhibitors
Mingming Wu ∙ Shiyue Yang ∙ Zhentao Yang ∙ … ∙ Douglas B. Johnson ∙ Sixue Liu ∙ Roger S. Lo
Immunity Published:October 31, 2025
DOI:https://doi.org/10.1016/j.immuni.2025.10.001
Graphical abstract
Highlights
- Acquired-resistant melanomas amplify anti-apoptotic and/or delete pro-apoptotic genes
- Models of acquired ICI resistance recapitulate apoptotic evasion due to CNVs
- Preexisting and de novo resistance-driver CNVs occur commonly or privately in subclones
- Lowering the apoptotic threshold salvages ICI sensitivity and prevents relapse
Summary
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.
