Local, but not circulating, complement C3 shapes immune checkpoint blockade efficacy by controlling myeloid cell...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• The complement system protein C3 is crucial for immune defense, with its gene predating the circulatory system.
• While hepatocyte-derived C3's role is known, the function of locally produced C3 remains largely undefined.

Purpose of the Study:

• To investigate the specific role of locally produced C3 in cancer immunotherapy efficacy.
• To elucidate the mechanisms by which C3 influences anti-PD-1 therapy response.

Main Methods:

• Utilized cancer-associated fibroblast (CAF)-specific C3 knockout mouse models for colorectal and lung tumors.
• Analyzed tumor immune microenvironment, focusing on macrophage infiltration and complement receptor 3 (CR3) signaling.
• Investigated the impact of targeting the iC3b/CR3 pathway on anti-PD-1 therapy response in resistant tumors.
• Correlated stromal C3 expression with immunotherapeutic outcomes in human cancers.

Main Results:

• CAF-derived C3, not hepatocyte-derived C3, significantly impacts anti-PD-1 therapy efficacy.
• Tumors in CAF-specific C3 knockout mice showed resistance to anti-PD-1 therapy, characterized by increased immunosuppressive M2-like macrophages.
• The C3 degradation product iC3b was found to suppress myeloid cell infiltration via CR3 signaling.
• Therapeutic targeting of the iC3b/CR3 pathway restored sensitivity to PD-1 blockade in resistant mouse tumors.
• In human cancers, stromal C3 expression correlated with reduced M2-like macrophages and better immunotherapy outcomes.

Conclusions:

• Locally produced C3 by CAFs plays a critical role in modulating the tumor immune microenvironment and response to cancer immunotherapy.
• The iC3b/CR3 signaling pathway represents a potential therapeutic target to overcome immunotherapy resistance.
• These findings highlight a conserved role for local C3 in innate immunity across species.