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

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.

• Authors: 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 Boulter, Sam M Janes, Simon Wilkinson, Juan Carlos Acosta
• Journal: Cell reports (Cell Rep) Vol. 41 Issue 6 Pg. 111596 (11 08 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 36351380 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Toll-Like Receptor 2

Topics

• Mice
• Animals
• Humans
• Toll-Like Receptor 2 (genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (genetics)
• Lung Neoplasms (genetics)
• Genes, Tumor Suppressor
• Lung (metabolism)
• Cellular Senescence (genetics)