Diacylglycerol kinase α inhibition cooperates with PD-1-targeted therapies to restore the T cell activation program

Background Antibody-based therapies blocking the programmed cell death-1/ligand-1 (PD-1/PD-L1) axis have provided unprecedent clinical success in cancer treatment. Acquired resistance, however, frequently occurs, commonly associated with the upregulation of additional inhibitory molecules. Diacylglycerol kinase (DGK) α limits the extent of Ras activation in response to antigen recognition, and its upregulation facilitates hypofunctional, exhausted T cell states. Pharmacological DGK α targeting restores cytotoxic function of chimeric antigen receptor and CD8 + T cells isolated from solid tumors, suggesting a mechanism to reverse T cell exhausted phenotypes. Nevertheless, the contribution of DGK α downstream of the PD-1/PD-L1 inhibitory axis in human T cells and the consequences of combining DGK α and anti-PD-1/PD-L1 inhibitors are still unresolved relevant issues. Materials and methods We used a human triple parameter reporter cell line to investigate DGK α contribution to the PD-1/PD-L1 inhibitory pathway. We also addressed the impact of deleting DGK α expression in the growth dynamics and systemic tumor-derived effects of a PD-1-related tumor model, the MC38 colon adenocarcinoma. Results We identify DGK α as a contributor to the PD-1/PD-L1 axis that strongly limits the Ras/ERK/AP-1 pathway. DGK α function reinforces exhausted T cell phenotypes ultimately promoting tumor growth and generalized immunosuppression. Pharmacological DGKα inhibition selectively enhances AP-1 transcription and, importantly, cooperates with antibodies blocking the PD-1/PD-L1 interrelation. Conclusions Our results indicate that DGK α inhibition could provide an important mechanism to revert exhausted T lymphocyte phenotypes and thus favor proper anti-tumor T cell responses. The cooperative effect observed after PD-1/PD-L1 and DGK α blockade offers a promising strategy to improve the efficacy of immunotherapy in the treatment of cancer.