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) alpha limits the extent of Ras activation in response to antigen recognition, and its upregulation facilitates hypofunctional, exhausted T cell states. Pharmacological DGK alpha 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 alpha downstream of the PD-1/PD-L1 inhibitory axis in human T cells and the consequences of combining DGK alpha 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 alpha contribution to the PD-1/PD-L1 inhibitory pathway. We also addressed the impact of deleting DGK alpha 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 alpha as a contributor to the PD-1/PD-L1 axis that strongly limits the Ras/ERK/AP-1 pathway. DGK alpha function reinforces exhausted T cell phenotypes ultimately promoting tumor growth and generalized immunosuppression. Pharmacological DGK alpha inhibition selectively enhances AP-1 transcription and, importantly, cooperates with antibodies blocking the PD-1/PD-L1 interrelation. Conclusions Our results indicate that DGK alpha 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 alpha blockade offers a promising strategy to improve the efficacy of immunotherapy in the treatment of cancer.