Human endogenous retroviruses and their implication for immunotherapeutics of cancer

A.S. Attermann, AM. Bjerregaard, S.K. Saini, K. Grønbæk, S.R. Hadrup*

*Corresponding author for this work

    Research output: Contribution to journalJournal articleResearchpeer-review

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    Abstract

    Human endogenous retroviruses (HERVs) have recently caught increased attention as a potential internal trigger to sensitize tumor cells to immunotherapies. HERVs are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny. Today, HERVs constitute ∼8% of the human genome, but most elements are highly degenerated, under strict epigenetic regulation, and rarely expressed in healthy tissues. However, cancer cells are specifically prone to reactivate the expression of HERV elements due to epigenetic dysregulation that accumulate during malignant transformation and when using epigenetic therapies. HERV expression can induce an interferon response due to induction of the viral defense pathway, so-called ‘viral mimicry’. By mimicking viral infections, HERVs could function as an ‘intrinsic adjuvant’, possibly sensitizing cancer cells to immunological recognition. Furthermore, translated HERV elements may in themselves form a valuable pool of tumor-associated antigens. Epitopes derived from HERVs have been recognized by cytotoxic CD8+ T cells, leading to cancer cell recognition. The combination of ‘viral mimicry’ and T-cell recognition could provide a powerful combination with existing immune stimulatory therapies, such as checkpoint inhibition. This combination is currently being evaluated in clinical trials in a large number of cancers.
    Original languageEnglish
    JournalAnnals of Oncology
    Volume29
    Issue number11
    Pages (from-to)2183–2191
    ISSN0923-7534
    DOIs
    Publication statusPublished - 2018

    Keywords

    • Cancer immunotherapy
    • HERV
    • Combination therapy
    • Immune checkpoint inhibitors
    • DNA methyltransferase inhibitors
    • Tumor-associated antigens

    Cite this

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    title = "Human endogenous retroviruses and their implication for immunotherapeutics of cancer",
    abstract = "Human endogenous retroviruses (HERVs) have recently caught increased attention as a potential internal trigger to sensitize tumor cells to immunotherapies. HERVs are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny. Today, HERVs constitute ∼8{\%} of the human genome, but most elements are highly degenerated, under strict epigenetic regulation, and rarely expressed in healthy tissues. However, cancer cells are specifically prone to reactivate the expression of HERV elements due to epigenetic dysregulation that accumulate during malignant transformation and when using epigenetic therapies. HERV expression can induce an interferon response due to induction of the viral defense pathway, so-called ‘viral mimicry’. By mimicking viral infections, HERVs could function as an ‘intrinsic adjuvant’, possibly sensitizing cancer cells to immunological recognition. Furthermore, translated HERV elements may in themselves form a valuable pool of tumor-associated antigens. Epitopes derived from HERVs have been recognized by cytotoxic CD8+ T cells, leading to cancer cell recognition. The combination of ‘viral mimicry’ and T-cell recognition could provide a powerful combination with existing immune stimulatory therapies, such as checkpoint inhibition. This combination is currently being evaluated in clinical trials in a large number of cancers.",
    keywords = "Cancer immunotherapy, HERV, Combination therapy, Immune checkpoint inhibitors, DNA methyltransferase inhibitors, Tumor-associated antigens",
    author = "A.S. Attermann and AM. Bjerregaard and S.K. Saini and K. Gr{\o}nb{\ae}k and S.R. Hadrup",
    year = "2018",
    doi = "10.1093/annonc/mdy413",
    language = "English",
    volume = "29",
    pages = "2183–2191",
    journal = "Annals of Oncology",
    issn = "0923-7534",
    publisher = "Oxford University Press",
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    }

    Human endogenous retroviruses and their implication for immunotherapeutics of cancer. / Attermann, A.S.; Bjerregaard, AM.; Saini, S.K.; Grønbæk, K.; Hadrup, S.R.

    In: Annals of Oncology, Vol. 29, No. 11, 2018, p. 2183–2191.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Human endogenous retroviruses and their implication for immunotherapeutics of cancer

    AU - Attermann, A.S.

    AU - Bjerregaard, AM.

    AU - Saini, S.K.

    AU - Grønbæk, K.

    AU - Hadrup, S.R.

    PY - 2018

    Y1 - 2018

    N2 - Human endogenous retroviruses (HERVs) have recently caught increased attention as a potential internal trigger to sensitize tumor cells to immunotherapies. HERVs are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny. Today, HERVs constitute ∼8% of the human genome, but most elements are highly degenerated, under strict epigenetic regulation, and rarely expressed in healthy tissues. However, cancer cells are specifically prone to reactivate the expression of HERV elements due to epigenetic dysregulation that accumulate during malignant transformation and when using epigenetic therapies. HERV expression can induce an interferon response due to induction of the viral defense pathway, so-called ‘viral mimicry’. By mimicking viral infections, HERVs could function as an ‘intrinsic adjuvant’, possibly sensitizing cancer cells to immunological recognition. Furthermore, translated HERV elements may in themselves form a valuable pool of tumor-associated antigens. Epitopes derived from HERVs have been recognized by cytotoxic CD8+ T cells, leading to cancer cell recognition. The combination of ‘viral mimicry’ and T-cell recognition could provide a powerful combination with existing immune stimulatory therapies, such as checkpoint inhibition. This combination is currently being evaluated in clinical trials in a large number of cancers.

    AB - Human endogenous retroviruses (HERVs) have recently caught increased attention as a potential internal trigger to sensitize tumor cells to immunotherapies. HERVs are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny. Today, HERVs constitute ∼8% of the human genome, but most elements are highly degenerated, under strict epigenetic regulation, and rarely expressed in healthy tissues. However, cancer cells are specifically prone to reactivate the expression of HERV elements due to epigenetic dysregulation that accumulate during malignant transformation and when using epigenetic therapies. HERV expression can induce an interferon response due to induction of the viral defense pathway, so-called ‘viral mimicry’. By mimicking viral infections, HERVs could function as an ‘intrinsic adjuvant’, possibly sensitizing cancer cells to immunological recognition. Furthermore, translated HERV elements may in themselves form a valuable pool of tumor-associated antigens. Epitopes derived from HERVs have been recognized by cytotoxic CD8+ T cells, leading to cancer cell recognition. The combination of ‘viral mimicry’ and T-cell recognition could provide a powerful combination with existing immune stimulatory therapies, such as checkpoint inhibition. This combination is currently being evaluated in clinical trials in a large number of cancers.

    KW - Cancer immunotherapy

    KW - HERV

    KW - Combination therapy

    KW - Immune checkpoint inhibitors

    KW - DNA methyltransferase inhibitors

    KW - Tumor-associated antigens

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    JO - Annals of Oncology

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