<scp>BET</scp> inhibition sensitizes innate checkpoint inhibitor resistant melanoma to <scp>anti‐CTLA</scp>‐4 treatment-Reference-Cited by-同舟云学术

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

Published:2024-05-09 Issue: Volume: Page:
ISSN:1755-1471
Container-title:Pigment Cell & Melanoma Research
language:en
Short-container-title:Pigment Cell Melanoma Res

Author:

Tseng Hsin‐Yi¹²³^ORCID,Alavi Sara¹²³^ORCID,Gallagher Stuart¹²³⁴^ORCID,McGuire Helen M.²⁴⁵^ORCID,Hersey Peter²³^ORCID,Al Emran Abdullah¹²⁶^ORCID,Tiffen Jessamy¹³⁴^ORCID

Affiliation:

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

Abstract

AbstractApproximately 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.

Funder

Cancer Council NSW

Cancer Institute NSW

Publisher

Wiley

Link

https://onlinelibrary.wiley.com/doi/pdf/10.1111/pcmr.13174

Reference26 articles.

1. Nicotinamide Inhibits T Cell Exhaustion and Increases Differentiation of CD8 Effector T Cells

2. Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma

3. A Combination of Epigenetic BET and CDK9 Inhibitors for Treatment of Human Melanoma

4. Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy