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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1246-1256.e8
Number of pages	19
Journal	Journal of Investigative Dermatology
Volume	143
Issue number	7
DOIs	https://doi.org/10.1016/j.jid.2023.01.017
Publication status	Published - Jul 2023

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10.1016/j.jid.2023.01.017

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@article{495ade6b6b1e4e02b43f73b0910a2ac6,

title = "IFN-γ signaling sensitizes melanoma cells to BH3 mimetics",

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.",

author = "Zizhen Ming and Lim, \{Su Yin\} and Ashleigh Stewart and Bernadette Pedersen and Elena Shklovskaya and Menzies, \{Alexander M.\} and Carlino, \{Matteo S.\} and Kefford, \{Richard F.\} and Lee, \{Jenny H.\} and Scolyer, \{Richard A.\} and Long, \{Georgina V.\} and Helen Rizos",

year = "2023",

month = jul,

doi = "10.1016/j.jid.2023.01.017",

language = "English",

volume = "143",

pages = "1246--1256.e8",

journal = "Journal of Investigative Dermatology",

issn = "0022-202X",

publisher = "Elsevier",

number = "7",

}

TY - JOUR

T1 - IFN-γ signaling sensitizes melanoma cells to BH3 mimetics

AU - Ming, Zizhen

AU - Lim, Su Yin

AU - Stewart, Ashleigh

AU - Pedersen, Bernadette

AU - Shklovskaya, Elena

AU - Menzies, Alexander M.

AU - Carlino, Matteo S.

AU - Kefford, Richard F.

AU - Lee, Jenny H.

AU - Scolyer, Richard A.

AU - Long, Georgina V.

AU - Rizos, Helen

PY - 2023/7

Y1 - 2023/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85150357971

UR - https://purl.org/au-research/grants/nhmrc/1093017

UR - https://purl.org/au-research/grants/nhmrc/1128951

UR - https://purl.org/au-research/grants/nhmrc/1130423

U2 - 10.1016/j.jid.2023.01.017

DO - 10.1016/j.jid.2023.01.017

M3 - Article

C2 - 36736995

AN - SCOPUS:85150357971

SN - 0022-202X

VL - 143

SP - 1246-1256.e8

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 7

ER -

IFN-γ signaling sensitizes melanoma cells to BH3 mimetics

Abstract

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Molecular determinants of risk, progression and treatment response in melanoma

Acquired resistance to PD1 inhibition in melanoma

Determinants of response to immune checkpoint inhibitors in melanoma

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IFN-γ signaling sensitizes melanoma cells to BH3 mimetics

Abstract

Access to Document

Other files and links

Fingerprint

Projects

Molecular determinants of risk, progression and treatment response in melanoma

Acquired resistance to PD1 inhibition in melanoma

Determinants of response to immune checkpoint inhibitors in melanoma

Cite this