The Francis Crick Institute
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Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer.

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journal contribution
posted on 2023-05-11, 10:07 authored by Clare E Weeden, Velimir Gayevskiy, Claire Marceaux, Daniel Batey, Tania Tan, Kenta Yokote, Nina Tubau Ribera, Allison Clatch, Susan Christo, Charis E Teh, Andrew J Mitchell, Marie Trussart, Lucille C Rankin, Andreas Obers, Jackson A McDonald, Kate D Sutherland, Varun J Sharma, Graham Starkey, Rohit D'Costa, Phillip Antippa, Tracy Leong, Daniel Steinfort, Louis Irving, Charles Swanton, Claire L Gordon, Laura K Mackay, Terence P Speed, Daniel HD Gray, Marie-Liesse Asselin-Labat
Tissue-resident memory T (TRM) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and whether TRM cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a TRM-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander TRM-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.


Crick (Grant ID: CC2041, Grant title: Swanton CC2041) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS) Novo Nordisk UK Research Foundation (Grant ID: NNF15OC0016584, Grant title: NovoNordisk Foundation 16584)