1. The T cell differentiation landscape is shaped by tumour mutations in lung cancer
- Author
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Ghorani, E, Reading, JL, Henry, JY, de Massy, MR, Rosenthal, R, Turati, V, Joshi, K, Furness, AJS, Aissa, AB, Saini, SK, Ramskov, S, Georgiou, A, Sunderland, MW, Wong, YNS, De Mucha, MV, Day, W, Galvez-Cancino, F, Becker, PD, Uddin, I, Ismail, M, Ronel, T, Woolston, A, Jamal-Hanjani, M, Veeriah, S, Birkbak, NJ, Wilson, GA, Litchfield, K, Conde, L, Guerra-Assuncao, JA, Blighe, K, Biswas, D, Salgado, R, Lund, T, Al Bakir, M, Moore, DA, Hiley, CT, Loi, S, Sun, Y, Yuan, Y, AbdulJabbar, K, Turajilic, S, Herrero, J, Enver, T, Hadrup, SR, Hackshaw, A, Peggs, KS, McGranahan, N, Chain, B, Swanton, C, Quezada, SA, Ghorani, E, Reading, JL, Henry, JY, de Massy, MR, Rosenthal, R, Turati, V, Joshi, K, Furness, AJS, Aissa, AB, Saini, SK, Ramskov, S, Georgiou, A, Sunderland, MW, Wong, YNS, De Mucha, MV, Day, W, Galvez-Cancino, F, Becker, PD, Uddin, I, Ismail, M, Ronel, T, Woolston, A, Jamal-Hanjani, M, Veeriah, S, Birkbak, NJ, Wilson, GA, Litchfield, K, Conde, L, Guerra-Assuncao, JA, Blighe, K, Biswas, D, Salgado, R, Lund, T, Al Bakir, M, Moore, DA, Hiley, CT, Loi, S, Sun, Y, Yuan, Y, AbdulJabbar, K, Turajilic, S, Herrero, J, Enver, T, Hadrup, SR, Hackshaw, A, Peggs, KS, McGranahan, N, Chain, B, Swanton, C, and Quezada, SA
- Abstract
Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.
- Published
- 2020