LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade

Sheng, Wanqiang; LaFleur, Martin W.; Nguyen, Thao H.; Chen, Sujun; Chakravarthy, Ankur; Conway, Jake R.; Liu, Ying; Chen, Hao; Yang, Henry; Hsu, Pang-Hung; Allen, Eliezer M. Van; Freeman, Gordon J.; Carvalho, Daniel D. De; He, Housheng Hansen; Sharpe, Arlene H.; Shi, Yang

doi:10.1016/j.cell.2018.05.052

Cited by 525 publications

(549 citation statements)

References 42 publications

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“…Expression of such ERVs promoted MHC class 1 upregulation, T‐cell infiltration, activation of immune checkpoints, and myeloid infiltration, thus promoting tumor immune suppression. On the other hand, Sheng et al demonstrated that expression of ERVs was increased following ablation of the histone demethylase LSD1 in cancer cells, which led to dsRNA stress and activation of type 1 IFNs, stimulated antitumor T‐cell immunity, and restrained tumor growth in return . Further studies are still warranted to elucidate the detailed role of HERVs in regulating immunity.…”

Section: Functional Roles Of Hervs In Carcinogenesismentioning

confidence: 99%

Expressional activation and functional roles of human endogenous retroviruses in cancers

Zhang

Liang

Zheng

2019

Reviews in Medical Virology

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Summary Human endogenous retroviruses (HERVs) are widely believed to be remnants of ancestral germ line infections by exogenous retroviruses. Although HERVs are deemed as “nonfunctional DNAs” due to loss of most of their viral protein coding capacity during evolution as part of the human genome, cumulative evidences are showing the expressional activation and potential roles of HERVs in diseases especially cancers. Work by other researchers and us has observed the dysregulation of HERVs in cancers, identified new HERV‐related genes, and revealed their potential importance in cancer development. Here, we summarized the current knowledge on the mechanisms of the expressional activation and functional roles of HERVs, with a focus on the H family HERV (HERV‐H), in carcinogenesis. HERV expression is regulated by external chemical or physical substances and exogenous virus infection, as well as host factors such as epigenetic DNA methylation, transcription factors, cytokines, and small RNAs. Diverse roles of HERVs have been proposed by acting in the forms of noncoding RNAs, proteins, and transcriptional regulators during carcinogenesis. However, much remains to be learnt about the contributions of HERVs to human cancers. More investigation is warranted to elucidate the functions of these “fossil remnants” yet important viral DNAs in the human genome.

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Section: Functional Roles Of Hervs In Carcinogenesismentioning

confidence: 99%

Expressional activation and functional roles of human endogenous retroviruses in cancers

Zhang

Liang

Zheng

2019

Reviews in Medical Virology

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“…Specifically, it has been shown that ablation of histone demethylase LSD1 activates type I interferon, which stimulates anti-tumor T cell immunity. This elicits significant responses to checkpoint blockade in mouse melanomas which were previously refractory to anti-PD-1 therapy 165 . Similarly, the combination of interferon and anti-CTLA4 antibody had superior efficacy compared to anti-CTLA4 antibody alone in a phase Ib trial of melanoma patients 166 .…”

Section: Future Directions In Treatment With Immune Checkpoint Inhibimentioning

confidence: 99%

The challenges of checkpoint inhibition in the treatment of multiple myeloma

Paul

Kang

Zheng

et al. 2018

Cellular Immunology

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Despite significant improvements in the overall survival of patients with multiple myeloma (MM) over the past 15 years, the disease remains incurable. Treatment options are limited for patients who have relapsed or are refractory to immunomodulatory drugs (IMiDs), proteasome inhibitors, and monoclonal antibodies. In these patients, immunotherapies such as checkpoint inhibitors, oncolytic vaccines, and chimeric antigen receptor (CAR) T cells provide a potentially effective alternative treatment. While checkpoint inhibitors are effective in prolonging overall survival in some patients with advanced solid cancers and Hodgkin lymphoma, they have not demonstrated significant anti-myeloma activities as a single agent in MM. In fact the combination of checkpoint inhibitors with IMiDs was recently found to increase the risk of death in myeloma patients. These challenges highlight the need for a better understanding of immune dysregulation in myeloma patients, and the mechanisms of action of- and resistance to- checkpoint inhibitors. In this review, we summarize immune dysfunction in patients with MM, and review the preclinical and clinical data regarding checkpoint inhibitors in myeloma. We conclude by proposing strategies to improve the efficacy and safety of checkpoint inhibitors in this population.

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“…The accumulation of double-stranded RNA (dsRNA) results in the stimulation of interferon (IFN) -dependent immunogenic responses (51). These studies also show that LSD1 inhibition overcomes resistance to checkpoint blockade therapy in vivo by increasing tumor immunogenicity and T cell infiltration (51)(52)(53). Several studies have shown interaction between LSD1 and SWI/SNF complexes.…”

Section: Introductionmentioning

confidence: 98%

“…Further, recent studies indicate that LSD1 ablation can trigger anti-tumor immunity through stimulation of expression of endogenous retroviral elements (ERVs) and downregulation of expression of the RNA-induced silencing complex (RISC). The accumulation of double-stranded RNA (dsRNA) results in the stimulation of interferon (IFN) -dependent immunogenic responses (51). These studies also show that LSD1 inhibition overcomes resistance to checkpoint blockade therapy in vivo by increasing tumor immunogenicity and T cell infiltration (51)(52)(53).…”

Section: Introductionmentioning

confidence: 98%

The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer

Soldi

Halder

Weston

et al. 2020

Preprint

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Chromatin remodeling SWItch/Sucrose-NonFermentable (SWI/SNF) complexes, initially identified in yeast 20 years ago, are evolutionarily conserved multi-subunit protein complexes that use the energy from hydrolysis of adenosine triphosphate (ATP) to remodel nucleosome structure and modulate transcription. Mutations in proteins of SWI/SNF complexes occur in 20% of human cancers including ovarian cancer (OC). Approximately 50% of ovarian clear cell carcinoma (OCCC) carries mutations in the SWI/SNF subunit ARID1A while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is driven primarily by genetic inactivation of the SWI/SNF ATPase SMARCA4 (BRG1) alongside epigenetic silencing of the homolog ATPase SMARCA2 (BRM). Dual loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may alsointerfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/SNF activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A) which regulates the chromatin landscape and gene expression by demethylating proteins, including histone H3. LSD1 associates with epigenetic complexes such as the nucleosome remodeling deacetylase complex (NuRD) and SWI/SNF to inhibit the transcription of genes involved in tumor suppression and cell differentiation. TGCA analysis of human cancers shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. Further, SCCOHT and OCCC cell lines show low nM IC 50 s for the reversible LSD1 inhibitor SP-2577 (Seclidemstat, currently in clinical phase I trials), supporting that these SWI/SNF-deficient ovarian cancers are dependent on LSD1 activity. Recently, it has been also shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of Endogenous Retroviruses Elements (ERVs) and may thereby overcome resistance to checkpoint blockade. Additionally, SCCOHTs have been shown to exhibit an immune-active tumor microenvironment with PD-L1 expression in both tumor and stromal cells that strongly correlated with T cell infiltration. Thus, in this study we investigated the ability of SP-2577 to promote anti-tumor immunity and T cell infiltration in SWI/SNF-mutant SCCOHT and OCCC models. Our data shows that the reversible LSD1 inhibitor SP-2577 stimulates IFN-dependent anti-tumor immunity in SCCOHT cells in vitro in a 3D immuneorganoid platform. Additionally, SP-2577 promoted the expression of PD-L1 in both SCCOHT and OCCC models. Together our findings suggest that SP-2577 and checkpoint inhibitors as a therapeutic combination may induce or augment immunogenic responses in these tumors.

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LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade

Cited by 525 publications

References 42 publications

Expressional activation and functional roles of human endogenous retroviruses in cancers

Expressional activation and functional roles of human endogenous retroviruses in cancers

The challenges of checkpoint inhibition in the treatment of multiple myeloma

The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer

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