IFN-γ Signaling Sensitizes Melanoma Cells to BH3 Mimetics

Zizhen Ming; Su Yin Lim; Ashleigh Stewart; Bernadette Pedersen; Elena Shklovskaya; Alexander M Menzies; Matteo S Carlino; Richard F Kefford; Jenny H Lee; Richard A Scolyer; Georgina V Long; Helen Rizos

doi:10.1016/j.jid.2023.01.017

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.

Affiliations

¹ Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, Australia.
² Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, Australia; Department of Medical Oncology, Mater Hospital, Sydney, Australia.
³ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australia; Department of Medical Oncology, Blacktown Cancer and Haematology Centre, Blacktown Hospital, Sydney, Australia.
⁴ Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Chris O'Brien Lifehouse, Camperdown, Australia.
⁵ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, Australia; Charles Perkins Centre, The University of Sydney, Sydney, Australia.
⁶ Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, Australia; Department of Medical Oncology, Mater Hospital, Sydney, Australia; Charles Perkins Centre, The University of Sydney, Sydney, Australia.
⁷ Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, Australia. Electronic address: helen.rizos@mq.edu.au.

PMID: 36736995
DOI: 10.1016/j.jid.2023.01.017

Abstract

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*

Substances

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