Endogenous retroviruses in the origins and treatment of cancer

Jansz, Natasha; Faulkner, Geoffrey J.

doi:10.1186/s13059-021-02357-4

Cited by 102 publications

(86 citation statements)

References 195 publications

(259 reference statements)

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“…It should be noted that there are caveats to using mouse models to study ERVs as tumor antigens. While infectious copies of recombined ERVs are common in mice (44,(52)(53)(54)(55)77), human ERVs (HERVs) so far appear to be inactive (42), which could alter the kinetics of antigen expression. Nevertheless, HERVs have long been studied in association with cancer (78)(79)(80)(81).…”

Section: Discussionmentioning

confidence: 99%

Identification of highly cross-reactive mimotopes for a public T cell response in murine melanoma

Grace

Backlund

Morgan

et al. 2022

Preprint

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While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8+ T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell response in vivo, engineered antigen mimotopes induced a significant expansion of CD8+ T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells in vivo yet showed modest survival benefit in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and generation of mimotopes which can induce robust functional T cell responses that are cross-reactive to the endogenous antigen across multiple individuals.

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Section: Discussionmentioning

confidence: 99%

Identification of highly cross-reactive mimotopes for a public T cell response in murine melanoma

Grace

Backlund

Morgan

et al. 2022

Preprint

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“…TE‐derived cis‐ regulatory sequences also enable p53 to have chromatin pioneering activity that allows p53 to initiate novel gene expression programmes (Sammons et al , 2015 ; Yu & Buck, 2019 ). This could include antiviral and tumour‐suppressive activities or oncogenic and anti‐inflammatory activities or the generation of neo‐antigens (Levine et al , 2016 ; Wylie et al , 2016 ; Buzdin et al , 2017 ; Lemaître et al , 2017 ; Garcia‐Montojo et al , 2018 ; Grandi & Tramontano, 2018 ; Tiwari et al , 2018 ; Xue et al , 2020 ; Jansz & Faulkner, 2021 ).…”

Section: P53 Isoforms Viruses and Other Pathogensmentioning

confidence: 99%

Adaptive homeostasis and the p53 isoform network

et al. 2021

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All living organisms have developed processes to sense and address environmental changes to maintain a stable internal state (homeostasis). When activated, the p53 tumour suppressor maintains cell and organ integrity and functions in response to homeostasis disruptors (stresses) such as infection, metabolic alterations and cellular damage. Thus, p53 plays a fundamental physiological role in maintaining organismal homeostasis. The TP53 gene encodes a network of proteins (p53 isoforms) with similar and distinct biochemical functions. The p53 network carries out multiple biological activities enabling cooperation between individual cells required for long‐term survival of multicellular organisms (animals) in response to an ever‐changing environment caused by mutation, infection, metabolic alteration or damage. In this review, we suggest that the p53 network has evolved as an adaptive response to pathogen infections and other environmental selection pressures.

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“…Since the studied melanoma cell line was obtained from a metastatic lesion of a nonresponding patient undergoing MAGE-3.A1 T-cell-based peptide immunotherapy, the authors postulated that hypermethylation-induced loss of HLA class I expression may be the cause of the impaired response to vaccination; however, this study highlights for the first time that DNMTis should be tested for their efficiency on reversing the acquired resistance to immunotherapy in CM [ 271 ]. Other preclinical studies have shown that DNMTi may trigger the activation of ERVs, which are normally transcriptionally silenced, leading to the activation of a type I IFN response and cytotoxic T cell recruitment into the TME [ 196 , 272 ]. DNMTi treatments were also linked with CTA induction in melanoma cells, with important pharmacological applications in CM management, as the homogeneous expression of a therapeutic target in neoplastic cells is a prerequisite to effectively target tumors by vaccination-induced CTA-directed immune response [ 273 ].…”

Section: Epigenetics-based Therapies For CMmentioning

confidence: 99%

Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma

Dobre

Constantin

Costache

et al. 2021

JPM

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Epigenetic alterations have emerged as essential contributors in the pathogenesis of various human diseases, including cutaneous melanoma (CM). Unlike genetic changes, epigenetic modifications are highly dynamic and reversible and thus easy to regulate. Here, we present a comprehensive review of the latest research findings on the role of genetic and epigenetic alterations in CM initiation and development. We believe that a better understanding of how aberrant DNA methylation and histone modifications, along with other molecular processes, affect the genesis and clinical behavior of CM can provide the clinical management of this disease a wide range of diagnostic and prognostic biomarkers, as well as potential therapeutic targets that can be used to prevent or abrogate drug resistance. We will also approach the modalities by which these epigenetic alterations can be used to customize the therapeutic algorithms in CM, the current status of epi-therapies, and the preliminary results of epigenetic and traditional combinatorial pharmacological approaches in this fatal disease.

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Endogenous retroviruses in the origins and treatment of cancer

Cited by 102 publications

References 195 publications

Identification of highly cross-reactive mimotopes for a public T cell response in murine melanoma

Identification of highly cross-reactive mimotopes for a public T cell response in murine melanoma

Adaptive homeostasis and the p53 isoform network

Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma

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