Toll-like receptor 2 orchestrates a tumor suppressor response in non-small cell lung cancer

Fraser R. Millar, Adam Pennycuick, Morwenna Muir, Andrea Quintanilla, Priya Hari, Elisabeth Freyer, Philippe Gautier, Alison Meynert, Graeme Grimes, Carla Salomo Coll, Sofia Zdral, Stella Victorelli, Vitor H. Teixeira, John Connelly, João F. Passos, Marian A. Ros, William A.H. Wallace, Margaret C. Frame, Andrew H. Sims, Luke BoulterSam M. Janes, Simon Wilkinson, Juan Carlos Acosta

Research output: Contribution to journalArticlepeer-review

Abstract

Targeting early-stage lung cancer is vital to improve survival. However, the mechanisms and components of the early tumor suppressor response in lung cancer are not well understood. In this report, we study the role of Toll-like receptor 2 (TLR2), a regulator of oncogene-induced senescence, which is a key tumor suppressor response in premalignancy. Using human lung cancer samples and genetically engineered mouse models, we show that TLR2 is active early in lung tumorigenesis, where it correlates with improved survival and clinical regression. Mechanistically, TLR2 impairs early lung cancer progression via activation of cell intrinsic cell cycle arrest pathways and the proinflammatory senescence-associated secretory phenotype (SASP). The SASP regulates non-cell autonomous anti-tumor responses, such as immune surveillance of premalignant cells, and we observe impaired myeloid cell recruitment to lung tumors after Tlr2 loss. Last, we show that administration of a TLR2 agonist reduces lung tumor growth, highlighting TLR2 as a possible therapeutic target.

Original languageEnglish (US)
Article number111596
JournalCell reports
Volume41
Issue number6
DOIs
StatePublished - Nov 8 2022

Keywords

  • CP: Cancer
  • SASP
  • Toll-like receptor
  • cancer therapy
  • innate immune receptors
  • non-small cell lung cancer
  • premalignancy
  • senescence
  • senescence surveillance
  • tumor suppressor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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