Complement activation promoted by the lectin pathway mediates C3aR-dependent sarcoma progression and...

Area of Science:

• Immunology
• Oncology

Background:

• Complement system activation is implicated in tumor-promoting inflammation.
• The specific roles of complement pathways in sarcoma development are not fully understood.

Purpose of the Study:

• To systematically assess the involvement of complement activation and effector pathways in sarcoma development and progression.
• To investigate the impact of complement deficiencies on sarcoma susceptibility and the tumor microenvironment.

Main Methods:

• Utilized knockout mouse models deficient in various complement components (C3, MBL1/2, C4, C1q, Factor B) and complement receptors (C3aR, C5aR1, C5aR2).
• Assessed susceptibility to chemically induced and transplanted sarcomas.
• Analyzed tumor-infiltrating immune cells, including macrophages and T cells.
• Performed transcriptional profiling of sarcoma-infiltrating myeloid cells.
• Correlated complement component expression and signatures with patient clinical outcomes.

Main Results:

• Mice deficient in C3, MBL1/2, or C4 exhibited reduced sarcoma development and growth.
• Deficiency in Complement 3a receptor (C3aR) mimicked the protective effects seen in C3-deficient mice.
• C3 and C3aR deficiency led to decreased pro-tumorigenic macrophages, enhanced T cell activation, and improved response to anti-PD-1 therapy.
• C3-deficient myeloid cells showed enriched antigen presentation pathways.
• In patients, C3aR expression correlated with macrophage signatures, and C3 deficiency-associated signatures predicted better outcomes.

Conclusions:

• The lectin pathway and the C3a/C3aR axis are critical drivers of complement-mediated sarcoma promotion.
• These pathways contribute to immunosuppression within the tumor microenvironment by influencing macrophages.
• Targeting the C3a/C3aR axis represents a potential therapeutic strategy for sarcoma treatment.