BET inhibition sensitizes innate checkpoint inhibitor resistant melanoma to anti-CTLA-4 treatment

Hsin-Yi Tseng; Sara Alavi; Stuart Gallagher; Helen M McGuire; Peter Hersey; Abdullah Al Emran; Jessamy Tiffen

doi:10.1111/pcmr.13174

BET inhibition sensitizes innate checkpoint inhibitor resistant melanoma to anti-CTLA-4 treatment

Pigment Cell Melanoma Res. 2024 May 9. doi: 10.1111/pcmr.13174. Online ahead of print.

Authors

Hsin-Yi Tseng^{1

2

3}, Sara Alavi^{1

2

3}, Stuart Gallagher^{1

2

3

4}, Helen M McGuire^{2

4

5}, Peter Hersey^{2

3}, Abdullah Al Emran^{1

2

6}, Jessamy Tiffen^{1

3

4}

Affiliations

¹ Melanoma Epigenetics Lab, the Centenary Institute, University of Sydney, Sydney, New South Wales, Australia.
² Melanoma Immunology and Oncology Program, The Centenary Institute, University of Sydney, Sydney, New South Wales, Australia.
³ Melanoma Institute Australia, Sydney, New South Wales, Australia.
⁴ Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia.
⁵ Ramaciotti Facility for Human Systems Biology, University of Sydney, Sydney, New South Wales, Australia.
⁶ Cutaneous Biology Research Centre, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

PMID: 38725219
DOI: 10.1111/pcmr.13174

Abstract

Approximately 50% of melanoma patients fail to respond to immune checkpoint blockade (ICB), and acquired resistance hampers long-term survival in about half of initially responding patients. Whether targeting BET reader proteins, implicated in epigenetic dysregulation, can enhance ICB response rates and durability, remains to be determined. Here we show elevated BET proteins correlate with poor survival and ICB responses in melanoma patients. The BET inhibitor IBET151, combined with anti-CTLA-4, overcame innate ICB resistance however, sequential BET inhibition failed against acquired resistance in mouse models. Combination treatment response in the innate resistance model induced changes in tumor-infiltrating immune cells, reducing myeloid-derived suppressor cells (MDSCs). CD4+ and CD8+ T cells showed decreased expression of inhibitory receptors, with reduced TIM3, LAG3, and BTLA checkpoint expression. In human PBMCs in vitro, BET inhibition reduced expression of immune checkpoints in CD4+ and CD8+ T cells, restoring effector cytokines and downregulating the transcriptional driver TOX. BET proteins in melanoma may play an oncogenic role by inducing immune suppression and driving T cell dysfunction. The study demonstrates an effective combination for innately unresponsive melanoma patients to checkpoint inhibitor immunotherapy, yet highlights BET inhibitors' limitations in an acquired resistance context.

Keywords: BET inhibitors; CTLA‐4 checkpoint inhibitor immunotherapy; T cell exhaustion; melanoma; therapy resistance.

Abstract

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