Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity

Xiong, Yan; Wang, Liqing; Giorgio, Eros Di; Akimova, Tatiana; Beier, Ulf H.; Han, Rongxiang; Trevisanut, Matteo; Kalin, Jay H.; Cole, Philip A.; Hancock, Wayne W.

doi:10.1172/jci131375

Cited by 51 publications

(55 citation statements)

References 49 publications

(59 reference statements)

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“…Remarkably, we find that inhibition of CoREST activity in human melanoma specifically inhibits both distinctive proliferative and invasive cellular phenotypes and that such inhibition promotes resensitization of treatment-resistant melanoma cells to targeted BRAF inhibition. We further note that corin treatment of tumors in immunocompetent mice promoted antitumor immunity and impaired Foxp3+ Treg function 16 , suggesting that a therapeutic strategy targeting CoREST might enhance anticancer effects both through direct effects on tumor phenotype plasticity as well as an enhanced immune response (Extended Data Fig. 4).…”

Section: Discussionmentioning

confidence: 80%

“…The CoREST repressor complex is a member of the class 1 histone deacetylase family of repressor complexes that was originally identified as a cofactor for REST repression and regulation of neuron-specific gene silencing during development 14 . RCOR1 functions as a scaffold for the CoREST repressor complex promoting crosstalk between HDAC1/2 and the H3K4me demethylase LSD1 15 , and has recently been shown to regulate Treg function and antitumor immunity 16 . We recently described a potent and specific dual-warhead inhibitor of the CoREST complex targeting HDAC1/2 and LSD1, corin, that demonstrates growth inhibition in melanoma, cutaneous squamous cell carcinoma 5 , and diffuse intrinsic pontine glioma.…”

Section: Mainmentioning

confidence: 99%

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The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma

Hanly

Gibson

et al. 2020

Preprint

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Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through non-mutational events1,2. Although the epigenetic landscape has been shown to be altered in therapy-resistant melanomas and other cancers3,4, a specific targetable epigenetic mechanism regulating treatment resistance has not been validated to date. Here we evaluate the CoREST repressor complex and the novel inhibitor, corin5, within the context of melanoma phenotype plasticity and therapeutic resistance in order to define epigenetic mechanisms underlying these processes. We find that CoREST is a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells leads to phenotype reprogramming. We further demonstrate that treatment of BRAF inhibitor (BRAFi)-resistant melanomas with corin leads to resensitization of tumor cells to BRAFi. Among the transcriptional targets of CoREST in melanoma are the dual-specificity phosphatases (DUSPs). DUSP1 is shown to be consistently downregulated in BRAFi-resistant melanomas which can be reversed by corin treatment, thereby leading to downstream inhibition of p38 MAPK activity and resensitization of resistant cells to targeted BRAFi therapies. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial to patients with BRAF-mutant melanomas who have acquired BRAFi-resistance.

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Section: Discussionmentioning

confidence: 80%

Section: Mainmentioning

confidence: 99%

The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma

Hanly

Gibson

et al. 2020

Preprint

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“…Specific deletion of the core gene Rcor1 in mice led to decreased Treg suppressive function in vivo and in vitro, and a decrease of Hdac2 and Lsd1 enzymes. The decreased Hdac2 and Lsd1 increased the acetylation of histone3 at T‐bet promoter, which promote the expression of Th1‐signature cytokine IFN‐γ 43 . While CoREST functions as a repressive factor, inhibition of CoREST enhanced the antitumour immunity mainly by an epigenetic mechanism.…”

Section: Molecular Mechanism Accounting For Impaired Suppressive Funcmentioning

confidence: 99%

Molecular mechanism for impaired suppressive function of Tregs in autoimmune diseases: A summary of cell‐intrinsic and cell‐extrinsic factors

Yang

Wang

Xia

2020

J Cellular Molecular Medi

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Regulatory T cells (Tregs) are a subset of CD4 + T cells which exerts immunosuppressive functions. Tregs are essential in maintaining the self-tolerance and cell homeostasis in healthy individuals. Although surface molecules like CD25 and CD127, and immune checkpoint molecules such as CTLA4, GITR and LAG-3 have been suggested as the markers of Tregs, accumulating evidences suggest that their expression are not Treg-specific. For example, upon activation, CTLA-4, GITR and LAG-3 are expressed on all CD4 + T cells. 1 Controversial opinions have been proposed on regarding Foxp3 as a marker of Tregs. Despite the fact that a population of Foxp3 + CD4 + T cells do not express CD25, Foxp3 expression is more abundant in CD4 + CD25 + Treg cells. The importance of role of Foxp3 in the development of Tregs has been noticed since mutation of Foxp3 has been found to lead to severe multiorgan autoimmune syndromes including XLAAD and IPEX. 2 Moreover, Foxp3 expression is essential for the Treg signature and immunosuppressive function.

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“…The class I HDAC inhibitor Entinostat, currently under investigation in different types of cancer, was shown to decrease Foxp3 expression in vitro and in vivo [115]. Similarly, chemical inhibition or genetic ablation of REST Corepressor 1 (Rcor 1) in Treg cells that leads to disruption of HDAC1 and HDAC2 activity, promotes the expression of inflammatory cytokines by Treg cells, and impairs their ability to suppress anti-tumor immunity [116]. Finally, it was shown that genetic ablation of the histone/protein acetyltransferase p300 specifically in Treg cells, delays the growth of transplanted tumors, while autoimmune symptoms remain mild and non-lethal [117].…”

Section: Epigenetic Programing Of Treg Cells In Cancermentioning

confidence: 99%

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

Stéphan¹,

Lautraite²,

Voisin³

et al. 2020

Cancers

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Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators.

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Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity

Cited by 51 publications

References 49 publications

The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma

The CoREST Repressor Complex Mediates Phenotype Switching and Therapy Resistance in Melanoma

Molecular mechanism for impaired suppressive function of Tregs in autoimmune diseases: A summary of cell‐intrinsic and cell‐extrinsic factors

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

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