Understanding signal modulation by the inhibitory immune checkpoints (360G-Wellcome-215883_Z_19_Z)

£300,000

Immune checkpoint proteins expressed on the surface of T-cells fine-tune signaling from the T-cell receptor by providing co-stimulatory and inhibitory signals. The manipulation of the receptors that provide the inhibitory signals (‘inhibitory receptors’), using interaction-blocking and agonistic antibodies, holds great promise for treating cancer and autoimmunity. Remarkably little is known, however, about the signaling pathways initiated by the inhibitory receptors, or how their expression at the cell surface is regulated following signaling. Important, unanswered questions therefore are: (1) what makes inhibitory receptors inhibitory - are there shared or convergent inhibitory pathways that can be targeted systematically; and (2) if we want to agonize these receptors, can their downregulation be prevented so that signaling is sustained? This proposal aims to characterize the signaling and surface-modulatory behavior of a set of five immune checkpoints using systematic genetic screens. I will use reporter cell-lines generated to study inhibitory signaling pathways in T-cells to identify the genetic regulators of inhibitory signaling and receptor down-modulation induced by native ligands and by antibody agonists, using a CRISPR/Cas9-based, genome-scale loss-of-function screening approach. The project should yield new insights into how inhibitory signals are generated, and how they might be better harnessed for treating malignancies and autoimmunity.

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Grant Details

Amount Awarded 300000
Applicant Surname Sharma
Approval Committee Basic Science Interview Committee
Award Date 2019-04-24T00:00:00+00:00
Financial Year 2018/19
Grant Programme: Title Sir Henry Wellcome Postdoctoral Fellowship
Internal ID 215883/Z/19/Z
Lead Applicant Dr Sumana Sharma
Partnership Value 300000
Planned Dates: End Date 2025-02-07T00:00:00+00:00
Planned Dates: Start Date 2020-05-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East
Sponsor(s) Prof Simon Davis