Teriflunomide modulates the PD-1/PD-L1 axis and enhances antitumor immunity in colorectal cancer

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• The PD-1/PD-L1 pathway is crucial in cancer immunotherapy, but limited patient response necessitates novel modulators.
• Colorectal cancer (CRC) remains a significant health challenge, with immunotherapy response varying among patients.

Purpose of the Study:

• To investigate teriflunomide (TER), an FDA-approved drug, as a novel immune checkpoint modulator for CRC treatment.
• To assess TER's effects on PD-L1 expression, PD-1 binding, CD8+ T-cell function, and antitumor activity in CRC models.

Main Methods:

• TER's impact on PD-L1 expression was evaluated in human CRC cell lines.
• Direct binding of TER to PD-1 and its effect on CD8+ T-cell function were assessed.
• Antitumor activity was studied in vivo using a humanized mouse model (hPD-1 KI mice with MC38 tumor cells).

Main Results:

• TER reduced PD-L1 expression in CRC cells and directly disrupted the PD-1/PD-L1 interaction.
• In vivo, TER significantly suppressed tumor growth without systemic toxicity.
• TER enhanced CD8+ T-cell infiltration and activation (indicated by granzyme B expression) within tumors, crucial for its antitumor effect.

Conclusions:

• Teriflunomide (TER) acts as a potent immune checkpoint modulator targeting the PD-1/PD-L1 axis.
• TER promotes CD8+ T-cell-mediated antitumor immunity, offering a promising therapeutic strategy for CRC.
• TER's established safety profile makes it a readily translatable option for enhancing cancer immunotherapy in CRC.