IFN-γ Signaling Sensitizes Melanoma Cells to BH3 Mimetics

J Invest Dermatol. 2023 Jul;143(7):1246-1256.e8. doi: 10.1016/j.jid.2023.01.017. Epub 2023 Feb 1.


Immunotherapy targeting PD-1 and/or CTLA4 leads to durable responses in a proportion of patients with melanoma. However, many patients will not respond to these immune checkpoint inhibitors, and up to 60% of responding patients will develop treatment resistance. We describe a vulnerability in melanoma driven by immune cell activity that provides a pathway towards additional treatment options. This study evaluated short-term melanoma cell lines (referred to as PD1 PROG cells) derived from melanoma metastases that progressed on PD-1 inhibitor-based therapy. We show that the cytokine IFN-γ primes melanoma cells for apoptosis by promoting changes in the accumulation and interactions of apoptotic regulators MCL-1, NOXA, and BAK. The addition of pro-apoptotic BH3 mimetic drugs sensitized PD1 PROG melanoma cells to apoptosis in response to IFN-γ or autologous immune cell activation. These findings provide translatable strategies for combination therapies in melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Line, Tumor
  • Humans
  • Interferon-gamma
  • Melanoma* / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein / therapeutic use
  • Proto-Oncogene Proteins c-bcl-2*


  • Proto-Oncogene Proteins c-bcl-2
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Apoptosis Regulatory Proteins
  • Interferon-gamma