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.
Abbreviation:
KO (knockout)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Investigative DermatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression.Ann Oncol. 2018; 29: 1575-1581
- Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: Updated findings of LEAP-004.J Clin Oncol. 2021; 39: 9504
- Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma.Nat Med. 2019; 25: 941-946
- Interferon-gamma induces X-linked inhibitor of apoptosis-associated factor-1 and Noxa expression and potentiates human vascular smooth muscle cell apoptosis by STAT3 activation.J Biol Chem. 2008; 283: 6832-6842
- Cytokines tumor necrosis factor-α and interferon-γ induce pancreatic β-cell apoptosis through STAT1-mediated Bim protein activation.J Biol Chem. 2011; 286: 39632-39643
- Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade.Cell. 2016; 167: 1540-1554.e12
- Immune checkpoint inhibitors in melanoma.Lancet. 2021; 398: 1002-1014
- Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.Mol Cell. 2005; 17: 393-403
- Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.Nat Rev Mol Cell Biol. 2014; 15: 49-63
- Azacitidine and venetoclax in previously untreated acute myeloid leukemia.N Engl J Med. 2020; 383: 617-629
- Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i.Nat Med. 2020; 26: 1557-1563
- Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy.Cell. 2016; 167: 397-404.e9
- Conserved interferon-γ signaling drives clinical response to immune checkpoint blockade therapy in melanoma.Cancer Cell. 2020; 38: 500-515.e3
- Venetoclax ex vivo functional profiling predicts improved progression-free survival.Blood Cancer J. 2022; 12: 115
- Venetoclax: evidence to date and clinical potential.Drugs Context. 2019; 8: 212574
- Venetoclax increases intratumoral effector T cells and antitumor efficacy in combination with immune checkpoint blockade.Cancer Discov. 2021; 11: 68-79
- The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.Nature. 2016; 538: 477-482
- Five-year survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2019; 381: 1535-1546
- Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition.Nat Commun. 2020; 11: 1897
- the pan-Bcl-2 inhibitor sensitizes hepatocellular carcinoma cells to promote the anti-tumor efficacy in combination with immune checkpoint blockade.Transl Oncol. 2021; 14: 101116
- The Molecular Signatures Database (MSigDB) hallmark gene set collection.Cell Syst. 2015; 1: 417-425
- Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047).J Clin Oncol. 2021; 39: 9503
- BH3-mimetic drugs: blazing the trail for new cancer medicines.Cancer Cell. 2018; 34: 879-891
- The dark side of IFN-γ: its role in promoting cancer immunoevasion.Int J Mol Sci. 2017; 19
- Exploiting MCL1 dependency with combination MEK + MCL1 inhibitors leads to induction of apoptosis and tumor regression in KRAS-mutant non-small cell lung cancer.Cancer Discov. 2018; 8: 1598-1613
- An inhibitor of Bcl-2 family proteins induces regression of solid tumours.Nature. 2005; 435: 677-681
- Development and maintenance of B and T lymphocytes requires anti-apoptotic MCL-1.Nature. 2003; 426: 671-676
- An immunogenic personal neoantigen vaccine for patients with melanoma.Nature. 2017; 547: 217-221
- Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy.Cell. 2017; 170: 1109-1119.e10
- Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.Lancet Oncol. 2019; 20: 1239-1251
- Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia.N Engl J Med. 2016; 374: 311-322
- Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors.Nat Commun. 2019; 10: 5167
- iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.Lancet Oncol. 2017; 18: e143-e152
- Primary resistance to PD-1 blockade mediated by JAK1/2 mutations.Cancer Discov. 2017; 7: 188-201
- Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions.Nat Commun. 2017; 8: 15440
- Interferon-gamma induces microglial-activation-induced cell death: a hypothetical mechanism of relapse and remission in multiple sclerosis.Neurobiol Dis. 2006; 22: 33-39
- Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq.Science. 2016; 352: 189-196
- ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.Cancer Res. 2008; 68: 3421-3428
- Co-targeting bromodomain and extra-terminal proteins and MCL1 induces synergistic cell death in melanoma.Int J Cancer. 2020; 147: 2176-2189
- Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins.Genes Dev. 2005; 19: 1294-1305
- Mutations associated with acquired resistance to PD-1 blockade in melanoma.N Engl J Med. 2016; 375: 819-829
- LIGHT/IFN-γ triggers β cells apoptosis via NF-κB/Bcl2-dependent mitochondrial pathway.J Cell Mol Med. 2016; 20: 1861-1871
Supplementary References
- Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.Nature. 2009; 462: 108-112
- Evaluating strategies to normalise biological replicates of Western blot data.PLoS One. 2014; 9e87293
- Interferon-γ-mediated growth regulation of melanoma cells: involvement of STAT1-dependent and STAT1-independent signals.J Invest Dermatol. 2004; 122: 414-422
- Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition.Nat Commun. 2020; 11: 1897
- Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.Proc Natl Acad Sci USA. 2005; 102: 15545-15550
Article info
Publication history
Published online: February 01, 2023
Accepted:
January 5,
2023
Received in revised form:
December 22,
2022
Received:
October 2,
2022
accepted manuscript published online XXX; corrected proof published online XXXPublication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
