Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours

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Description

<jats:title>Abstract</jats:title><jats:p>Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16<jats:sup>Ink4a</jats:sup>/p19<jats:sup>Arf</jats:sup>(<jats:italic>Cdkn2a</jats:italic>) or p21<jats:sup>Cip1</jats:sup>(<jats:italic>Cdkn1a</jats:italic>) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication.</jats:p>

Journal

  • Nature Communications

    Nature Communications 11 (1), 1335-, 2020-03-12

    Springer Science and Business Media LLC

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