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Unit Programme: Defining the mechanism of toxicity from loss of immune checkpoints

Dr. James Thaventhiran 

Immunotherapy for the treatment of infection, autoimmunity and cancer targets adaptive immune lymphocytes and it is the individual response of specific clones of these cells that provides immunological memory. These treatments need to be improved, as not all patients respond and in those that respond drug-toxicity is often life-limiting. Our aims are to

1) Determine the distinguishing characteristics of beneficial and harmful adaptive immune responses.

2) Contrast the mechanisms by which harmful versus beneficial clonal immunity develops.

We use a combination approach for these studies using human samples to define the characteristics of lymphocytes in disease states and preclinical models to determine mechanisms by which these states arise. Our approach to these studies is distinctive: In patient samples, we compare the immunophenotype of tissue from cancer immunotherapy treated patients and rare-patients who have single-gene defects in immunotherapy targets. Allowing us to distinguish true on-target effects via off-target side effects. For our preclinical studies, we use a bespoke system developed in-house for tracking the fate of individual clones of responding lymphocytes that can be applied to diverse immunological challenges. State of the art analytical approaches for these studies are used including single-cell RNA sequencing, multi-dimensional flow cytometry and whole-genome sequencing.

This focus on fundamental mechanisms, allows us to rapidly respond to emergent priorities and our current application to COVID-19 research is yielding novel insights into how this disease is best treated.

Selected Reports1-3

 

1          Thaventhiran, J. E. D. et al. Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature 583, 90-95, doi:10.1038/s41586-020-2265-1 (2020).

2          Spencer, S. et al. Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. J Exp Med 216, 1986-1998, doi:10.1084/jem.20190344 (2019).

3          Biasci, D., Thaventhiran, J. & Tavaré, S. Fibroblastic reticular cells predict response to cancer immunotherapy. bioRxiv (2020).