Anatomy and Neuroscience - Research Publications

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Author: Irving, Louis × Author: Steinfort, Daniel × Author: Leong, Tracy Li-Tsein × Author: Asselin-Labat, Marie-Liesse ×

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    Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer
    Weeden, CE ; Gayevskiy, V ; Marceaux, C ; Batey, D ; Tan, T ; Yokote, K ; Ribera, NT ; Clatch, A ; Christo, S ; Teh, CE ; Mitchell, AJ ; Trussart, M ; Rankin, LC ; Obers, A ; McDonald, JA ; Sutherland, KD ; Sharma, VJ ; Starkey, G ; D'Costa, R ; Antippa, P ; Leong, T ; Steinfort, D ; Irviing, L ; Swanton, C ; Gordon, CL ; Mackay, LK ; Speed, TP ; Gray, DHD ; Asselin-Labat, M-L (CELL PRESS, 2023-05-08)
    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.
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    Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer
    Leong, TL ; Gayevskiy, V ; Steinfort, DP ; De Massy, MR ; Gonzalez-Rajal, A ; Marini, KD ; Stone, E ; Chin, V ; Havryk, A ; Plit, M ; Irving, LB ; Jennings, BR ; McCloy, RA ; Jayasekara, WSN ; Alamgeer, M ; Boolell, V ; Field, A ; Russell, PA ; Kumar, B ; Gough, DJ ; Szczepny, A ; Ganju, V ; Rossello, FJ ; Cain, JE ; Papenfuss, AT ; Asselin-Labat, M-L ; Cowley, MJ ; Watkins, DN (SPRINGERNATURE, 2019-03-07)
    Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.