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

Area of Science:

• Immunology
• Metabolic reprogramming
• Cancer research

Background:

• Stress significantly impacts cancer progression and treatment efficacy.
• The relationship between stress, metabolic changes, and the immune system in cancer is not fully understood.
• Dipeptidyl peptidase-4 (DPP4) is implicated in metabolic and immune functions.

Purpose of the Study:

• To investigate the effect of stress on DPP4 activity.
• To determine the role of DPP4 in stress-induced immune alterations in cancer.
• To evaluate DPP4 inhibition as a therapeutic strategy in stressed cancer models.

Main Methods:

• Utilized a repeated social defeat stress model in mice.
• Analyzed circulating corticosterone, blood glucose, and plasma DPP4 activity.
• Conducted cohort studies correlating psychological distress with DPP4 activity in cancer patients.
• Investigated DPP4 inhibition effects on immune cell populations, vaccine efficacy, and anti-tumor responses.
• Performed proteome profiling of mouse plasma.

Main Results:

• Stress increased circulating corticosterone, blood glucose, and plasma DPP4 activity.
• Plasma DPP4 activity correlated with psychological distress severity in cancer patients.
• DPP4 inhibition reversed stress-induced neutrophil and monocyte expansion.
• DPP4 blockade restored prophylactic tumor vaccine efficacy and augmented T cell priming.
• DPP4 blockade enhanced intratumoral CD8+ T cell and dendritic cell accumulation, cytokine production, and tumor antigen presentation.

Conclusions:

• Elevated DPP4 activity is a stress-induced metabolic change linked to immune dysregulation in cancer.
• Targeting DPP4 may be a viable strategy to enhance anti-tumor immunity in cancer patients experiencing psychological distress.
• DPP4 inhibition demonstrates therapeutic potential in mitigating stress-related immune suppression in cancer.