AbstractSignalling through co-inhibitory receptors is required to dampen inflammation at the end of an immune response. Suppression of CD8+ cytotoxic T lymphocyte responses is one mechanism by which inhibitory receptors downregulate inflammation. Within the tumour microenvironment, inhibitory receptor engagement occurs chronically and at high levels, such that CD8+ Tumour Infiltrating Lymphocytes (TILs) are suppressed within tumours.
In a murine renal carcinoma model (Renca), adoptive T cell transfer of tumour-specific CD8+ T cells, together with antagonists of two co-inhibitory receptors, were delivered as combination immunotherapy. Systemic blockade of both TIM3 and A2a-Adenosine Receptors resulted in complete tumour regression amongst RencaHA tumour-bearing mice; which was associated with an increase in the number of CD8+ TILs, reduced numbers of tumour-infiltrating FOXP3+ T-regulatory cells, and improved ex vivo cytotoxic function of CD8+ TILs. Moreover, blockade of TIM3 and A2aRs also led to the development of anti-tumour immune memory T cells, which enabled mice to resist rechallenge.
These data demonstrate that TIM3 and A2aR signalling synergise to inhibit the infiltration and cytotoxic effector function of anti-tumour CD8+ TILs, and that blockade of TIM3 and A2aRs may provide a novel immunotherapeutic strategy for the treatment of various human cancers.
|Date of Award
|1 Oct 2019
|David J Morgan (Supervisor) & Christoph Wuelfing (Supervisor)