IFN-y Signaling Sensitizes Melanoma Cells to BH3 Mimetics

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 shortterm 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-g 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-g or autologous immune cell activation. These findings provide translatable strategies for combination therapies in melanoma.

Automated summary

Immunotherapy targeting PD-1 and/or CTLA4 can lead to durable responses in some melanoma patients. However, treatment resistance and lack of response are common. This study identifies a vulnerability in melanoma driven by immune cell activity, providing potential strategies for combination therapies.