Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy

Li, Jing; Wang, Weichao; Zhang, Yajia; Cieślik, Marcin; Guo, Jipeng; Tan, Mengyao; Green, Michael D.; Wang, Weimin; Lin, Heng; Li, Wei; Wei, Shuang; Zhang, Jiajia; Li, Gaopeng; Jing, Xiaojun; Vatan, Linda; Zhao, Lili; Bitler, Benjamin G.; Zhang, Rugang; Cho, Kathleen R.; Dou, Yali; Kryczek, Ilona; Chan, Timothy A.; Huntsman, David G.; Chinnaiyan, Arul M.; Zou, Weiping

doi:10.1172/jci134402

Cited by 131 publications

(124 citation statements)

References 65 publications

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“…However, whether this association could be explained mechanistically by SWI/SNF mutations is unclear. Further studies are needed to clarify these findings in UTUC, given that the link between mutations in SWI/SNF genes and immunity is contradictory in different cancer subtypes [ 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive integrative profiling of upper tract urothelial carcinomas

Bazai

et al. 2021

Genome Biol

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Background Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood. Results We perform an integrative genome- and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carcinomas. In addition to mutations of FGFR3 and KDM6A, we identify ZFP36L1 as a novel, significantly mutated tumor suppressor gene. Overall, mutations of ZFP36 family genes (ZFP36, ZFP36L1, and ZFP36L2) are identified in 26.7% of cases, which display a high mutational load. Unsupervised DNA methylation subtype classification identifies two epi-clusters associated with distinct muscle-invasive status and patient outcome, namely, EpiC-low and EpiC-high. While the former is hypomethylated, immune-depleted, and enriched for FGFR3-mutated, the latter is hypermethylated, immune-infiltrated, and tightly associated with somatic mutations of SWI/SNF genes. Conclusions Our study delineates for the first time the key role for convergence between genetic and epigenetic alterations in shaping clinicopathological and immune upper tract urothelial carcinoma features.

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Section: Discussionmentioning

confidence: 99%

Comprehensive integrative profiling of upper tract urothelial carcinomas

Bazai

et al. 2021

Genome Biol

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“…Moreover, EZH2 inhibition enhances T cell-targeting immunotherapies in mouse models of melanoma 25,26 . Interestingly, ARID1A, a member of the SWI/SNF family is found to interact with EZH2 to inhibit IFN-responsiveness gene expression in cancer cells, whose mutations can shape cancer immune phenotype and immunotherapy 27 Here we find that Mi-2β played a key role in regulating adaptive immune response in melanoma. The human Mi-2β protein was discovered as autoantigens in dermatomyositis in 1995 28 .…”

Section: Introductionmentioning

confidence: 72%

“…Over recent years there has been increasing evidence that some chromatin regulatory factors are crucial in regulating resistance to anti-PD-1 antibody treatment in melanoma, 15 , such as EZH2 26 and ARID1A 27 . EZH2 inhibition enhances T cell-targeting immunotherapies in vivo 25,26 whereas ARID1A interacts with EZH2 to inhibit IFN-response gene expression in cancer cells 27 and CD40 are also regulated by Mi-2β, all of which are crucial in regulating immune response in melanoma. Specifically, TAP1 is a key factor to specifically restrict anti-tumor responses through recognizing MHC-1/β2m-peptide complex on tumor surface in immunotherapy 69,70,71 .…”

Section: Discussionmentioning

confidence: 99%

Mi-2β-targeted inhibition induces immunotherapy response in melanoma

Zhu¹,

Wang²,

Yao³

et al. 2020

Preprint

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Recent development of some new immune checkpoint inhibitors has been particularly successfully in melanoma, but the majority of melanoma patients exhibit resistance. Understanding and targeting the potential underlying mechanism/targets, especially the tumor-intrinsic modulators to convert resistant melanomas to immunotherapy sensitivity will potentially provide a significant improvement in patient outcome. Here, Mi-2β, a chromatin remodeling enzyme was identified as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Loss of Mi-2β rescued the immune response to immunotherapy in vivo. Mechanistically, targeting Mi-2β induced the adaptive immune response by transcriptionally enhancing expression of a set of IFN-γ-responsive genes including CXCL9, CXCL10 and IRF1. Finally, we developed a Mi-2β-targeted inhibitor Z36-MP5, which specifically and effectively induced a response to immune checkpoint blockades in otherwise resistant melanomas. Our work provides a new insight into the epigenetic regulation in adaptive immune response, and highlights a viable strategy to improve immunotherapies in melanoma.

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“…In this regard, the identification of biomarkers that predict patients who are more likely to respond to ICB therapy is of considerable importance. Recently, we and others have reported that SWI/SNF deficiency is related to sensitivity to immune checkpoint blockade (ICB) therapy, indicating the potential for use of the SWI/SNF complex as a target for cancer immunotherapy 6,[26][27][28][29] . These findings suggest a novel role for SWI/SNF in modulating anti-tumor immunity and imply that aberrations of SWI/SNF components may serve as biomarkers to predict patient response to clinical ICB therapy.…”

Section: Introductionmentioning

confidence: 99%

Emerging role of SWI/SNF complex deficiency as a target of immune checkpoint blockade in human cancers

et al. 2021

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Mammalian SWI/SNF complex is a key chromatin remodeler that reshapes nucleosomes and regulates DNA accessibility. Mutations in SWI/SNF subunits are found in a broad spectrum of human cancers; however, the mechanisms of how these aberrations of SWI/SNF complex would impact tumorigenesis and cancer therapeutics remain to be elucidated. Studies have demonstrated that immune checkpoint blockade (ICB) therapy is promising in cancer treatment. Nevertheless, suitable biomarkers that reliably predict the clinical response to ICB are still lacking. Emerging evidence has suggested that SWI/SNF components play novel roles in the regulation of anti-tumor immunity, and SWI/SNF deficiency can be therapeutically targeted by ICB. These findings manifest the prominence of the SWI/SNF complex as a stratification biomarker that predicts treatment (therapeutic) response to ICB. In this review, we summarize the recent advances in ICB therapy by harnessing the cancer-specific vulnerability elicited by SWI/SNF deficiency. We provide novel insights into a comprehensive understanding of the underlying mechanisms by which SWI/SNF functions as a modulator of anti-tumor immunity.

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Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy

Cited by 131 publications

References 65 publications

Comprehensive integrative profiling of upper tract urothelial carcinomas

Comprehensive integrative profiling of upper tract urothelial carcinomas

Mi-2β-targeted inhibition induces immunotherapy response in melanoma

Emerging role of SWI/SNF complex deficiency as a target of immune checkpoint blockade in human cancers

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