DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells

Yau, Helen Loo; Bell, Emma; Ettayebi, Ilias; Almeida, Felipe Campos de; Boukhaled, Giselle M.; Shen, Shu Yi; Allard, David; Morancho, Beatriz; Marhon, Sajid A.; Ishak, Charles A.; Gonzaga, Isabela Martins; Medina, Tiago da Silva; Singhania, Rajat; Chakravarthy, Ankur; Chen, Raymond; Mehdipour, Parinaz; Pommey, Sandra; Klein, Christian; Amarante-Mendes, Gustavo P.; Roulois, David; Arribas, Joaquı́n; Stagg, John; Brooks, David G.; Carvalho, Daniel D. De

doi:10.1016/j.molcel.2021.01.038

Cited by 64 publications

(56 citation statements)

References 65 publications

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“…Despite this, we observed a relatively large number of TEs becoming activated with treatment, consistent with previous studies in cancer cell lines 53 . Loss of DNA methylation at repetitive elements and expression of TEs has been shown to drive viral mimicry response in tumours treated with epigenetic therapies [27][28][29] . In agreement with studies in colorectal tumour cells 27,54 , our results indicate that treatment with Decitabine results in up-regulation of multiple immune pathways (Interferon and Inflammatory Response pathways), which could promote anti-tumour immunity.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic therapy targets the 3D epigenome in endocrine-resistant breast cancer

Achinger-Kawecka

Stirzaker

Chia

et al. 2021

Preprint

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Three-dimensional (3D) epigenome remodelling is emerging as an important mechanism of gene deregulation in cancer. However, its potential as a target to overcome cancer therapy resistance remains largely unaddressed. Here we show that treatment of endocrine-resistant estrogen receptor positive (ER+) breast cancer with an FDA-approved epigenetic therapy Decitabine (5-Aza-mC), results in genome-wide DNA hypomethylation and suppression of tumour growth in preclinical metastatic ER+ breast tumour xenograft models. Systematic integration of matched chromatin conformation capture (Hi-C), Promoter Capture Hi-C, RNA-seq and ER ChIP-seq data revealed widespread effects on epigenome deregulation, including de-compaction of higher order chromatin structure and loss of topologically associating domains (TAD) boundary insulation. Key enhancer ER binding sites were demethylated and re-activated after Decitabine treatment, resulting in new ER mediated enhancer-promoter interactions and concordant activation of tumour suppressive gene pathways. Importantly, we show that the activated ER target genes were also predictive of good outcome in multiple ER+ breast cancer clinical cohorts. Together our study reveals a previously undescribed mechanism of Decitabine in re-wiring DNA methylation-dependent 3D genome architecture resulting in suppression of tumour growth, and highlights the potential of epigenetic therapy in targeting ER+ endocrine-resistant breast cancer.

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Section: Discussionmentioning

confidence: 99%

Epigenetic therapy targets the 3D epigenome in endocrine-resistant breast cancer

Achinger-Kawecka

Stirzaker

Chia

et al. 2021

Preprint

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show abstract

“…Furthermore, we found that activated CD8 T cells, eosinophils, CD56dim natural killer cells, and activated B cells are good prognostic factors for EC, which is basically consistent with the research results of the previous research ( López-Janeiro et al, 2021 ). Activated CD8 T cells and eosinophils have been widely verified to have significant antitumor effects ( Sakkal et al, 2016 ; Loo Yau et al, 2021 ; Pauken et al, 2021 ). On the other hand, some reports have demonstrated reduced CD8 expression in cytotoxic tumor-infiltrating T cells, which could limit antigen presentation and adaptative immune response in EC ( Pascual-García et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Construction and Validation of a Ferroptosis-Related Prognostic Model for Endometrial Cancer

Wang

Chen

et al. 2021

Front. Genet.

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“…Additional preclinical stage 2 + 1 TCBs based on this format have been described, including ones that target HER2 147 , 148 or the p95 HER2 fragment. 149 The p95 HER2 fragment is only found on a portion of ~ 30–40% of HER2 +++ tumor cells, and as such can be considered a highly tumor-specific neoantigen.…”

Section: Applications In Cancer Immunotherapy: Dual Checkpoint Inhibitors T and Innate Cell Engaging Bispecifics And Tumor-targeted Co-stmentioning

confidence: 99%

Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins

Surowka

Schaefer

Klein

2021

mAbs

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Bispecific antibodies have recently attracted intense interest. CrossMab technology was described in 2011 as novel approach enabling correct antibody light-chain association with their respective heavy chain in bispecific antibodies, together with methods enabling correct heavy-chain association using existing pairs of antibodies. Since the original description, CrossMab technology has evolved in the past decade into one of the most mature, versatile, and broadly applied technologies in the field, and nearly 20 bispecific antibodies based on CrossMab technology developed by Roche and others have entered clinical trials. The most advanced of these are the Ang-2/VEGF bispecific antibody faricimab, currently undergoing regulatory review, and the CD20/CD3 T cell bispecific antibody glofitamab, currently in pivotal Phase 3 trials. In this review, we introduce the principles of CrossMab technology, including its application for the generation of bi-/multispecific antibodies with different geometries and mechanisms of action, and provide an overview of CrossMab-based therapeutics in clinical trials.

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DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells

Cited by 64 publications

References 65 publications

Epigenetic therapy targets the 3D epigenome in endocrine-resistant breast cancer

Epigenetic therapy targets the 3D epigenome in endocrine-resistant breast cancer

Construction and Validation of a Ferroptosis-Related Prognostic Model for Endometrial Cancer

Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins

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