Detection and targeting of early T and B cell dysfunction in pre invasive lung neoplasia

Primary Supervisor: James Reading, UCL

Secondary supervisor: Timothy Tree, King’s College London

Less than 5% of patients diagnosed with late-stage lung cancer will survive for 5 years. In contrast, over 50% of patients diagnosed at the earliest stage of disease will survive the same period (1), engendering a global drive towards early detection. Preinvasive lung neoplasia occurs prior to lung cancer and provides a window of opportunity to detect and prevent lung tumour development, however, methods for early detection and prevention are lacking.

We and others have recently discovered networks of tumour-specific T and B cell dysfunction in established cancers (2-3). However, the early defects in the adaptive immune response that allow tumour development remain a mystery. Recent data suggests that this early phase of immune failure is both detectable and targetable (4). This poorly characterised process could therefore be weaponised for early detection and targeting of preinvasive neoplasia to forge clinical strategies that will seek and destroy nascent neoplasia before cancer develops.

This project will use an innovative new approach to harness early phases of the adaptive anti-tumour immune response to develop novel methods of early lung cancer detection and prevention. The candidate will use a suite of cutting-edge single-cell T cell and B cell omics assays to study the nascent phases of adaptive immune dysfunction during tumour development and apply these technologies to a globally unique cohort of longitudinal clinical samples in the EARL, UCLH surveillance and ASCENT studies led by Professor Sam Janes.

The candidate will be a central figure in a comprehensively supported and enthusiastic new team of multidisciplinary scientists using state-of-the-art experimental and bioinformatics tools to generate early detection methods and novel, actionable drug targets for precision immunoprevention. The position will be based in the Tumour Immunodynamics group at UCL Cancer Institute, leverage additional antigen specific T cell scRNAseq platforms from the Tree lab at KCL (5) and include a placement at the Centre for Immunobiology at Queen Mary University London (Dr Louisa James) to access training B cell profiling tools. The project will use a combination of high dimensional flow cytometry, ATACseq, bulk and sc-RNAseq, TCRseq, BCRseq and ag-specific reactivity profiling; making full use of the extensive set of CRUK City Of London infrastructure cores.

This technical portfolio will provide the candidate with a broad set of advanced wet and dry Immunology skills.
The candidate will have the opportunity for placements in several additional groups across the globe including those specialising in early cancer detection, epigenetics and high throughput antigen specific immune reactivity profiling.

We hypothesise that i) T and B cell markers of tumour antigen engagement will classify the presence of developing tumours/ forecast cancer progression; and ii) that mechanisms of B and T cell dysfunction can be identified during early disease to reveal functional targets for next generation checkpoint blockade.

The candidate will perform a focused program of research to address three aims:

1. Development of T and B cell-based multivariate early detection biomarkers
2. Provide a blueprint of novel actionable targets to reverse early T and B cell dysfunction
3. Evaluate targets in primary 3D in vitro explant models via siRNA.

Candidate background

This project will suit a candidate with a background and /or interest in tumour immunology with enthusiasm for developing novel therapeutics. Wet or dry lab experience in T or B cell Immunology is highly desirable and candidates should demonstrate an exceptional level of commitment to develop new skills and work in an integrated, dynamic team.

Potential Research Placements

1. Sam Janes, UCL Cancer Institute
2. Rahul Roychoudhur, University of Cambridge
3. Louisa James, Centre of Immunobiology in the Blizard Institute, Queen Mary University of London

References

1. https://www.cancerresearchuk.org
2. Reading, JL*#., Gálvez-Cancino*, F., Swanton, R. C., Lladser, A., Peggs, K., & Quezada, S. (2018). The function & dysfunction of memory CD8+ T cells in tumor immunity. Immunological Reviews (2018) 283 doi:10.1111/imr.12657
3. Litchfield K*, Reading JL*, Puttick C* Thakkar K, Abbosh C, Bentham R, Watkins T, Rosenthal R, Biswas D,? Quezada SA, McGranahan N, Swanton C, Cell (Feb 2021) Meta-analysis of Tumour and T cell intrinsic determinants of sensitivity to checkpoint inhibition. https://doi.org/10.1016/j.cell.2021.01.002
4. Reading, JL*# Ghorani, E*.,. L., Henry, J. Y., Massy, M. R. D., Rosenthal, R., Turati, V., . . . Quezada, S. A.# (May 2020). The T cell differentiation landscape is shaped by tumour mutations in lung cancer. Nature Cancer (May 2020), 1(5), 546-561. doi:10.1038/s43018-020-0066-y
5. Mahil SK et al.Tree TIM#, Smith CH#.Lancet Rheumatol. 2021 The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study. Sep;3(9):e627-e637. doi: 10.1016/S2665-9913(21)00212-5. Epub 2021 Jul 8.