Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors

Leruste, Amaury; Tosello, Jimena; Ramos, Rodrigo Nalio; Tauziède‐Espariat, Arnault; Brohard, Solène; Han, Zhi-Yan; Beccaria, Kévin; Andrianteranagna, Mamy; Caudana, Pamela; Nikolić, Jovan; Chauvin, Céline; Niborski, Leticia Laura; Manrı́quez, V.; Richer, Wilfrid; Masliah‐Planchon, Julien; Grossetête-Lalami, Sandrine; Bohec, Mylène; Lameiras, Sonia; Baulande, Sylvain; Pouponnot, Célio; Coulomb, Aurore; Galmiche, Louise; Surdez, Didier; Servant, Nicolas; Helft, Julie; Sedlik, Christine; Puget, Stéphanie; Benaroch, Philippe; Delattre, Olivier; Waterfall, Joshua J.; Piaggio, Eliane; Bourdeaut, Franck

doi:10.1016/j.ccell.2019.10.008

Cited by 106 publications

(103 citation statements)

References 81 publications

(99 reference statements)

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“…Chiapinelli et al already demonstrated that aza-induced cryptic transcripts are highly immunogenic and can sensitize tumors to checkpoint immunotherapy [33], while Sheng et al showed that also histone demethylase LSD1-ablation increases cryptic transcripts, thereby enabling checkpoint blockade [56]. The mechanism underlying immunogenicity likely depends on the formation of dsRNA, which via a viral mimicry-mediated process activates the immune system [35,48,56]. In addition, some of these transcripts contain open-reading frames, which could translate into abnormal proteins that can be antigenic [48].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, in hypoxic tumors with high checkpoint expression, DNA methylation at TSS of cryptic transcripts was reduced and consequently, cryptic transcript expression increased. Since tumors with high checkpoint expression often respond to checkpoint immunotherapy, and as cryptic transcripts could sensitize tumors to checkpoint blockade [33,35], this suggests hypoxia-induced cryptic transcripts to play an important role in mediating the therapeutic effects exerted by checkpoint inhibitors. In contrast, immune-cold tumors characterized by low immune checkpoint expression were much less tolerant to cryptic transcript expression, showing high methylation at retrotransposon promoters.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of repeat transcripts has been linked to tumor foreignness [32], interferon (IFN) response [33][34][35], and enhanced cytolytic activity [36], all critical determinants of response to checkpoint immunotherapy. Similar to our own data, such transcripts were shown to increase dsRNA formation.…”

Section: Hypoxia and Repeat Transcript Expression Affect Tumor Immunomentioning

confidence: 99%

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DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance

et al. 2020

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Background: Hypoxia is pervasive in cancer and other diseases. Cells sense and adapt to hypoxia by activating hypoxia-inducible transcription factors (HIFs), but it is still an outstanding question why cell types differ in their transcriptional response to hypoxia. Results: We report that HIFs fail to bind CpG dinucleotides that are methylated in their consensus binding sequence, both in in vitro biochemical binding assays and in vivo studies of differentially methylated isogenic cell lines. Based on in silico structural modeling, we show that 5-methylcytosine indeed causes steric hindrance in the HIF binding pocket. A model wherein cell-type-specific methylation landscapes, as laid down by the differential expression and binding of other transcription factors under normoxia, control cell-type-specific hypoxia responses is observed. We also discover ectopic HIF binding sites in repeat regions which are normally methylated. Genetic and pharmacological DNA demethylation, but also cancer-associated DNA hypomethylation, expose these binding sites, inducing HIF-dependent expression of cryptic transcripts. In line with such cryptic transcripts being more prone to cause double-stranded RNA and viral mimicry, we observe low DNA methylation and high cryptic transcript expression in tumors with high immune checkpoint expression, but not in tumors with low immune checkpoint expression, where they would compromise tumor immunotolerance. In a low-immunogenic tumor model, DNA demethylation upregulates cryptic transcript expression in a HIF-dependent manner, causing immune activation and reducing tumor growth. Conclusions: Our data elucidate the mechanism underlying cell-type-specific responses to hypoxia and suggest DNA methylation and hypoxia to underlie tumor immunotolerance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Hypoxia and Repeat Transcript Expression Affect Tumor Immunomentioning

confidence: 99%

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DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance

et al. 2020

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“…HERVs could thus be involved in the response to checkpoint blockade in tumors characterized by a low mutational burden. It has recently been shown that in rhabdoid tumors, a pediatric cancer exhibiting one of the lowest mutational burden, the driver mutation characterized by a biallelic loss of SMARCB1 (a core member of a chromatin remodeler complex) triggers the expression of HERVs, explaining thus the unusual immune infiltration of these tumors, which is driven by the subsequent type III IFN response [67].…”

Section: Impact Of Hervs Expression In the Response To Immune Checkpomentioning

confidence: 99%

Human Endogenous Retroviruses (HERVs): Shaping the Innate Immune Response in Cancers

Alcazer

Bonaventura

Depil

2020

Cancers

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Human Endogenous Retroviruses (HERVs) are accounting for 8% of the human genome. These sequences are remnants from ancient germline infections by exogenous retroviruses. After million years of evolution and multiple integrations, HERVs have acquired many damages rendering them defective. At steady state, HERVs are mostly localized in the heterochromatin and silenced by methylation. Multiple conditions have been described to induce their reactivation, including auto-immune diseases and cancers. HERVs re-expression leads to RNA (simple and double-stranded) and DNA production (by reverse transcription), modulating the innate immune response. Some studies also argue for a role of HERVs in shaping the evolution of innate immunity, notably in the development of the interferon response. However, their exact role in the innate immune response, particularly in cancer, remains to be defined. In this review, we see how HERVs could be key-players in mounting an antitumor immune response. After a brief introduction on HERVs characteristics and biology, we review the different mechanisms by which HERVs can interact with the immune system, with a focus on the innate response. We then discuss the potential impact of HERVs expression on the innate immune response in cancer.

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“…Beyond epigenetic therapies, further drug targets have recently emerged. Despite the fact that rhabdoid tumours display low mutation frequencies, two recent studies found a substantial degree of immune cell infiltration and a response of ATRT to checkpoint blockade [86,120]. Thus, novel and extratumoural therapeutic opportunities exist and it is worthwhile studying them together with classical chemotherapy or epigenetic treatments as a future prospect.…”

Section: Summary and Perspectivementioning

confidence: 99%

Invited Review: Dysregulation of chromatin remodellers in paediatric brain tumours – SMARCB1 and beyond

Johann

2020

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 57-72 Dysregulation of chromatin remodellers in paediatric brain tumours -SMARCB1 and beyond Mutations in chromatin remodelling genes occur in approximately 25% of all human tumours (Kadoch et al. Nat Genet 45: 592-601, 2013). The spectrum of alterations is broad and comprises single nucleotide variants, insertion/deletions and more complex structural variations. The single most often affected remodelling complex is the SWI/SNF complex (SWItch/sucrose non-fermentable). In the field of paediatric neuro-oncology, the spectrum of affected genes implicated in epigenetic remodelling is narrower with SMARCB1 and SMARCA4 being the most frequent.The low mutation frequencies in many of the SWI/SNF mutant entities underline the fact that perturbed chromatin remodelling is the most salient factor in tumourigenesis and could thus be a potential therapeutic opportunity. Here, I review the genetic basis of aberrant chromatin remodelling in paediatric brain tumours and discuss their impact on the epigenome in the respective entities, mainly medulloblastomas and rhabdoid tumours. Aberrations described in-Rhabdoid tumours eletions/SNVs (95% of all cases) -rare entities: INI1 deficient chordomas (10-20% of all cases), CRINET (all cases) Figure 1. An overview on SWItch/sucrose non-fermentable aberrant paediatric entities. CRINET, cribriform neuroepithelial tumours. Dysregulation of chromatin remodellers in paediatric neurooncology 61 CNS CRINET Point mutations CNS CRINET, cribriform neuroepithelial tumours.

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Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors

Cited by 106 publications

References 81 publications

DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance

DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance

Human Endogenous Retroviruses (HERVs): Shaping the Innate Immune Response in Cancers

Invited Review: Dysregulation of chromatin remodellers in paediatric brain tumours – SMARCB1 and beyond

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