Elevated activity of plasma dipeptidyl peptidase 4 upon stress can be targeted to reverse tumor immunosuppression

The interplay between stress-induced metabolic reprogramming and perturbations in the cancer-immune dialogue is a challenging research topic with huge knowledge gaps to fill. In a repeated social defeat model, we discovered that circulating corticosterone, blood glucose, and plasma DPP4 activity were increased in stressed mice. Consistently, three independent cohort studies showed that plasma DPP4 activity was positively correlated with the severity of psychological distress of newly diagnosed cancer patients. Stress-induced surge of glucocorticoid can boost DPP4 activity via glucocorticoid receptor signaling without influencing Dpp4 transcription or the abundance of soluble DPP4. Albeit catalytic inhibition of DPP4 upon stress can’t normalize the behavioral pattern and glucocorticoid secretion, it managed to reverse the expansion of circulating neutrophils and monocytes, restored the efficacy of prophylactic tumor vaccine, and augmented the priming of tumor-antigen specific T cells. DPP4 blockade in the context of stress largely enhanced the intratumoral accumulation of CD8⁺T cells and DCs, cytokine production by CD8⁺T and NK cells in situ, and tumor antigen presentation in vitro. Proteome profiling of mouse plasma revealed stress-related DPP4-sensitive changes that can be linked to immunological alterations and disturbed protease network. Altogether, elevated DPP4 activity may be targeted in cancer patients with psychiatric comorbidities to boost anti-tumor immunity.