IFNγ signaling sensitizes melanoma cells to BH3 Mimetics.

Ming Z, Lim SY, Stewart A, Pedersen B, Shklovskaya E, Menzies AM, Carlino MS, Kefford RF, Lee JH, Scolyer RA, Long GV, Rizos H.  Journal of Investigative Dermatology, (Feb 01 2023), doi:https://doi.org/10.1016/j.jid.2023.01.017.


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.