Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Dendritic cell (DC)-mediated antigen presentation is crucial for activating tumor-specific T cells.
• Limited therapeutic options exist to specifically target and manipulate DC functions for cancer immunotherapy.
• Identifying drugs that target DCs presents a significant opportunity for advancing cancer treatment.

Purpose of the Study:

• To identify novel therapeutics targeting conventional type 1 dendritic cells (cDC1s) for cancer immunotherapy.
• To investigate the antitumor mechanisms of a candidate drug identified through network-based screening.

Main Methods:

• A network-based approach was employed to screen for therapeutics targeting cDC1s.
• The antitumor efficacy and mechanisms of the identified drug were evaluated using in vitro and in vivo models.
• Transcriptional programs in cDC1s during antigen presentation were analyzed.

Main Results:

• Sitagliptin, an anti-diabetic drug, was identified as a DC-targeting therapeutic.
• Sitagliptin demonstrated antitumor effects by enhancing cDC1-mediated antigen presentation and T-cell activation in mouse models.
• Mechanistically, sitagliptin inhibits dipeptidyl peptidase 4 (DPP4), preventing chemokine/cytokine degradation and augmenting DC activation.
• Sitagliptin use correlated with reduced tumor recurrence in human colorectal cancer patients.

Conclusions:

• Sitagliptin, through DPP4 inhibition, enhances antitumor immune responses by boosting cDC1 function.
• Sitagliptin shows potential for repurposing as an anti-cancer drug targeting dendritic cells.
• This study provides a promising new strategy for cancer immunotherapy by leveraging sitagliptin.