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UCL Cancer Institute

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Tumour Immunodynamics Research Group

The Reading lab is focused on unravelling defects in endogenous tumour antigen surveillance through cancer evolution.

Group Leader: Dr James Reading

Tumour Immunodynamics (TIDY) group


Research

T cells can detect and eliminate mutant cells that arise during our lifetime, but defects in this defence facilitate cancer development, progression and metastasis. Many of these defects remain a mystery, presenting an acute scientific challenge. Determining how key tumour reactive T cells are dysregulated in nascent and metastatic disease may pave the way for a new wave of precision immunoprevention and immunotherapy strategies.

Our research focuses on deciphering the progressive dysregulation of tissue resident and systemic CD4 and CD8 T cell responses to mutation encoded neoantigens from health to death, in several unique clinical cohorts representing a range of cancer types. By longitudinally profiling neoantigen-reactive T cells at the functional, transcriptional, phenotypic and epigenetic level we aim to discern novel biomarkers and actionable T cell-intrinsic targets to inform future preventative and therapeutic immuno-oncology regimens.

We recently discovered a program of neoantigen-driven intra-tumoural T cell dysfunction in primary non-small lung cancer (NSCLC), characterised by a tumour-mutational burden (TMB)-dependent conversion of progenitor (TCF1+) to exhausted (TOX+PD1hi) T cell subsets. We found that neoantigen-driven T cell dysfunction (Neo-Dys) defines adverse clinical outcomes in multiple cancers, consistent with a common pathway of fatal immune failure.

To extend this investigation we explored the neoantigen-reactive T cell-intrinsic mechanisms that confer sensitivity to checkpoint inhibition (CPI; i.e. PD-1 or CTLA-4 blockade) in a pan-cancer meta-analysis of over 1000 immunotherapy-treated patients. Our work revealed that neoantigen-reactive T cells expressing chemotactic (e.g. CXCL13, CCR5), type I IFN (FBXO6) and T cell inhibitory (SLA2, IKZF3) genes may promote positive clinical outcomes, consistent with a role for active T cell recruitment and TCR activation in driving CPI responses.

In addition, we underscored the immunogenicity of several neoantigen subtypes and, with our collaborators, are exploring how expression of these key neoepitopes converges with patterns of tumour evolution and T cell differentiation to govern immune elimination vs failure throughout disease. Finally, we are exploiting surgical resection and neoantigen vaccination as experimental models to assess the impact of (neo)antigen withdrawal and stimulation on T cell dysfunction and immune escape. By systematically analysing functional and dysfunctional neoantigen-specific T cell responses we ultimately hope to pinpoint and prevent the decay of anti-tumour immunity.


Tumour evolution

This video from CRUK explains more about finding immune cells that can tackle evolving cancers:

YouTube Widget Placeholderhttps://www.youtube.com/watch?v=ZPwrvPerxIk


TRACERx


The TRACERx study aims to uncover mechanisms of cancer evolution by analysing the intratumour heterogeneity in lung tumours from approximately 850 patients and tracking its evolutionary trajectory from diagnosis through to relapse.

Cancer Evolution image from Nature Portfolio

Selected publications


1. Meta-analysis of Tumour and T cell intrinsic mechanisms of sensitization to checkpoint inhibition. Kevin Litchfield*, James L Reading*, Clare Puttick*, Krupa Thakkar, Chris Abbosh, Robert Bentham, Thomas B. K. Watkins, Rachel Rosenthal, Dhruva Biswas, Andrew Rowan, Emilia Lim, Maise Al Bakir, Virginia Turati, José Afonso Guerra-Assunção, Lucia Conde, Andrew J.S. Furness, Sunil Kumar Saini, Sine R Hadrup, Javier Herrero, Se-Hoon Lee, Peter Van Loo, Tariq Enver, James Larkin, Matthew D. Hellmann, Samra Turajlic, Sergio Quezada, Nicholas McGranahan, Charles Swanton.
Cell. (2021) Feb 4;184(3):596-614.e14. doi: 10.1016/j.cell.2021.01.002.

2. Augmented expansion of Regulatory T cells from healthy and autoimmune subjects via adult progenitor cell co-culture. Reading, J. L*#, Roorbruck,. V*., Hull, C.M,*, Becker P.D., Beyens, J., Valentin-Torres, A., Boardman, D., Nova Lamperti, E., Lombardi, G., Deans, R., Ting AE,Tree. Biorxiv. (2020) Dec doi: 10.1101/2020.12.03.410316

3. Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. Kevin Litchfield*, James L. Reading*, Emilia L. Lim, Hang Xu, Po Liu, Maise Al-Bakir, Yien Ning Sophia Wong, Andrew Rowan, Samuel A. Funt, Taha Merghoub, David Perkins, Martin Lauss, Inge Marie Svane, Göran Jönsson, Javier Herrero, James Larkin, Sergio A. Quezada, Matthew D. Hellmann, Samra Turajlic & Charles Swanton*. Nat Commun., (2020). July  11 (1), 3800. Doi:10.1038/s41467-020-17526-5
*equal contribution

Nature Cancer journal cover May 2020

4. The T cell differentiation landscape is shaped by tumour mutations in lung cancer. Ghorani, E*, Reading, J. L.*#, Henry, J. Y., Massy, M. R. D., Rosenthal, R., Turati, V., Joshi, K., Furness, A., Ben Aissa, A., Kumar Saini, S. et alRamskov 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-Assunção 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. Nature Cancer (2020) May 1 (5), 546-561. Doi: 10.1038/s43018-020-0066-y
*equal contribution
 


5. Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer. Joshi K*, Robert de Massy M*, Ismail M*, Reading JL, Uddin I, Woolston A, Hatipoglu E, Oakes T, Rosenthal R, Peacock T, Ronel T, Noursadeghi M, Turati V, Furness AJS, Georgiou A, Wong YNS, Ben Aissa A, Werner Sunderland M, Jamal-Hanjani M, Veeriah S, Birkbak NJ, Wilson GA, Hiley CT, Ghorani E, Guerra-Assunção JA, Herrero J, Enver T, Hadrup SR, Hackshaw A, Peggs KS, McGranahan N, Swanton C, Quezada SA, Chain B. Nat Med. (2019) Oct;25(10):1549-1559. Doi: 10.1038/s41591-019-0592-2

6. Neoantigen-directed immune escape in lung cancer evolution. Rosenthal R, Cadieux EL*, Salgado R*, Bakir MA*, Moore DA*, Hiley CT*, Lund T*, Tanić M, Reading JL, Joshi K, Henry JY, Ghorani E, Wilson GA, Birkbak NJ, Jamal-Hanjani M, Veeriah S, Szallasi Z, Loi S, Hellmann MD, Feber A, Chain B, Herrero J, Quezada SA, Demeulemeester J, Van Loo P, Beck S, McGranahan N, Swanton C. Nature. (2019) March; Doi: 10.1038/s41586-019-1032-7

7. Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment. Wong YNS, Joshi K, Khetrapal P, Ismail M, Reading JL, Sunderland MW, Georgiou A, Furness AJS, Ben Aissa A, Ghorani E, Oakes T, Uddin I, Tan WS, Feber A, McGovern U, Swanton C, Freeman A, Marafioti T, Briggs TP, Kelly JD, Powles T, Peggs KS, Chain BM, Linch MD, Quezada S. J Exp Med. (2018) Nov 5;215(11):2748-2759. Doi: 10.1084/jem.20181003

8. The function and dysfunction of memory CD8+ T cells in tumor immunity. Reading, J. L*#, Gálvez-Cancino, F*., Swanton, R. C., Lladser, A., Peggs, K., & Quezada, S. Immunological Reviews (2018) May;283(1):194-212. Doi: 10.1111/imr.12657

9. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Turajlic S*, Litchfield K*, Xu H, Rosenthal R, McGranahan N, Reading JL, Wong YNS, Rowan A, Kanu N, Al Bakir M, Chambers T, Salgado R, Savas P, Loi S, Birkbak NJ, Sansregret L, Gore M, Larkin J, Quezada SA, Swanton C. Lancet Oncol. (2017) Aug;18(8):1009-1021. Doi: 10.1016/S1470-2045(17)30516-8

10. Too Much of a Good Thing? Chronic IFN Fuels Resistance to Cancer Immunotherapy. Reading, J. L., & Quezada, S. A. (2016). Immunity, 45 (6), 1181-1183. Doi: 10.1016/j.immuni.​2016.12.004