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

Nat Commun. 2020 Mar 12;11(1):1335. doi: 10.1038/s41467-020-14987-6.

Abstract

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 p16Ink4a/p19Arf (Cdkn2a) or p21Cip1 (Cdkn1a) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism
  • Cell Cycle*
  • Cell Line, Tumor
  • Cellular Senescence*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Humans
  • Immunotherapy
  • Interferons / metabolism*
  • Ki-67 Antigen / metabolism
  • Lymph Nodes / pathology
  • Melanoma / immunology*
  • Melanoma / pathology*
  • Melanoma / therapy
  • Melanoma / ultrastructure
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • STAT1 Transcription Factor / metabolism
  • Survival Analysis
  • Tumor Burden

Substances

  • Antigens, Neoplasm
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Ki-67 Antigen
  • RNA, Messenger
  • STAT1 Transcription Factor
  • Interferons