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1. The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Author

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

2. 2022 WUOF/SIU International Consultation on Urological Diseases: Genetics and Tumor Microenvironment of Renal Cell Carcinoma.

Author

Khaleel S, Ricketts C, Linehan WM, Ball M, Manley B, Turajilic S, Brugarolas J, and Hakimi A

Abstract

Renal cell carcinoma is a diverse group of diseases that can be distinguished by distinct histopathologic and genomic features. In this comprehensive review, we highlight recent advancements in our understanding of the genetic and microenvironmental hallmarks of kidney cancer. We begin with clear cell renal cell carcinoma (ccRCC), the most common subtype of this disease. We review the chromosomal and genetic alterations that drive initiation and progression of ccRCC, which has recently been shown to follow multiple highly conserved evolutionary trajectories that in turn impact disease progression and prognosis. We also review the diverse genetic events that define the many recently recognized rare subtypes within non-clear cell RCC. Finally, we discuss our evolving understanding of the ccRCC microenvironment, which has been revolutionized by recent bulk and single-cell transcriptomic analyses, suggesting potential biomarkers for guiding systemic therapy in the management of advanced ccRCC., Competing Interests: Competing Interests None declared.

Published
2022
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3. The T cell differentiation landscape is shaped by tumour mutations in lung cancer.

Author

Ghorani E, Reading JL, Henry JY, Massy MR, Rosenthal R, Turati V, Joshi K, Furness AJS, Ben Aissa A, Saini SK, Ramskov S, Georgiou A, Sunderland MW, Wong YNS, Mucha MV, Day W, Galvez-Cancino F, Becker PD, Uddin I, Oakes T, Ismail M, Ronel T, Woolston A, Jamal-Hanjani M, Veeriah S, Birkbak NJ, Wilson GA, Litchfield K, Conde L, Guerra-Assunção JA, Blighe K, Biswas D, Salgado R, Lund T, Bakir MA, 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

Subjects
B7-H1 Antigen genetics, Biomarkers, Tumor genetics, Cell Differentiation genetics, Humans, Mutation, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics
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., Competing Interests: Competing interest statement S.A.Q., K.S.P. and C.S. are co-founders of Achilles Therapeutics. C.S. receives grant support from Pfizer, AstraZeneca, BMS, Roche-Ventana and Boehringer-Ingelheim. C.S. has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, and the Sarah Cannon Research Institute. C.S. is a shareholder of Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options in and is co-founder of Achilles Therapeutics. R.R., N.M. and G.A.W. have stock options in and have consulted for Achilles Therapeutics. J.L.R and M.A.B have consulted for Achilles Therapeutics. P.D.B and M.W.S are employees of Achilles Therapeutics.

Published
2020
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