Blocking C5aR signaling promotes the anti-tumor efficacy of PD-1/PD-L1 blockade

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Anti-programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) therapies are successful cancer treatments.
• A significant portion of patients do not respond to PD-1/PD-L1 blockade, necessitating strategies to overcome resistance.

Purpose of the Study:

• To investigate the role of the complement system, specifically C5a, in response to anti-PD-1/PD-L1 therapy.
• To evaluate the potential of combining C5a blockade with PD-1/PD-L1 antibodies to enhance anti-tumor immunity.

Main Methods:

• Administration of anti-PD-1/PD-L1 antibodies in a preclinical cancer model.
• Assessment of complement system activation and C5a generation.
• Analysis of myeloid-derived suppressor cells (MDSCs) accumulation and function.
• Evaluation of combination therapy using C5a receptor (C5aR) antagonists and PD-1/PD-L1 antibodies.

Main Results:

• Anti-PD-1/PD-L1 antibodies triggered complement activation and significant C5a production.
• C5a enhanced the suppressive function of myeloid-derived suppressor cells (MDSCs) without altering their numbers.
• Combining C5a blockade with PD-1/PD-L1 antibodies substantially improved anti-tumor responses.

Conclusions:

• C5a plays an immunosuppressive role during PD-1/PD-L1 blockade therapy.
• Targeting the C5a-C5aR axis represents a promising strategy to overcome resistance and enhance the efficacy of immune checkpoint inhibitors.