Immunotherapy has transformed the landscape of cancer treatment, yet it is effective in only a minority of patients. FOXP3+ regulatory T cells (Tregs) are found in the tumour microenvironment (TME) of many solid cancers and are associated with a poor prognosis because they suppress an effective immune response against cancer cells. Over 20 clinical trials have targeted Treg function and migration in tumours, yet none have progressed due to poor responses or autoimmune side effects. Our study aims to test a new way of specifically targeting Treg cells in tumours, by selectively inducing their cell death via necroptosis, while sparing Tregs in other tissues.
Caspase-8 inhibition using genetic or pharmacological approaches revealed that mouse and human Tregs in certain inflammatory settings have a heightened sensitivity to necroptosis compared to conventional T cells (Teh et al., 2022). To test whether blocking Caspase-8 in Treg cells will improve anti-cancer responses, we challenged mice with conditional deletion of Caspase-8 in Treg cells (Casp8Δfoxp3) with an ectopic MC38 model of colorectal cancer. We observed a selective reduction of Treg cells within the TME, but not in the draining lymph nodes and other lymphoid organs, demonstrating that tumour Treg cells were exquisitely sensitive to Caspase-8 blockade. To translate these findings into the human context, we tested an FDA approved caspase inhibitor, Emricasan, could impact viability of cells in CRC patient-derived tumour fragments. We found that Treg cells in patient derived tumour fragments from CRC patients were selectively sensitive to Emricasan. Taken together, our results indicate that loss of Caspase-8 activity in Tregs specifically induces their necroptosis in the TME but not in other sites. Further exploration will determine whether pharmacological blocking of Caspase-8 would be a useful adjunct with standard-of-care immunotherapies, such as immune checkpoint blockade, to improve anti-cancer responses.