Targeting complement C5a to improve radiotherapy sensitivity in non-small cell lung cancer

Area of Science:

• Immunology
• Oncology
• Radiotherapy

Background:

• Radiotherapy (RT) resistance and tumor recurrence are significant challenges in cancer treatment.
• The immune system, including innate and adaptive components, plays a crucial role in RT's antitumor effects.
• Complement C5a/C5aR1 signaling influences the tumor microenvironment (TME) and may impact RT efficacy.

Purpose of the Study:

• To investigate the role of complement C5a/C5aR1 signaling in the TME following RT.
• To explore the potential of combining RT with C5aR1 inhibition to overcome radioresistance.
• To elucidate the underlying molecular mechanisms of RT-induced immune modulation.

Main Methods:

• Administered fractionated RT to Lewis lung carcinoma (LLC) tumor-bearing mice.
• Analyzed CD8+ T cell infiltration and gene expression in RT-treated tumors.
• Evaluated tumor growth and immune response in mice treated with RT and/or a C5aR1 inhibitor.
• Assessed C5a/C5aR1 expression and AKT/NF-κB pathway activation in radiated tissues.

Main Results:

• RT increased CD8+ T cell infiltration and activated local complement C5a/C5aR signaling.
• Combined RT and C5aR1 blockade enhanced radiosensitivity and anti-tumor immune responses.
• High C5aR1 expression on CD8+ T cells correlated with improved outcomes.
• The AKT/NF-κB pathway was identified as a key mediator of C5a/C5aR signaling in RT.

Conclusions:

• RT induces C5a release from tumor cells, upregulating C5aR1 via the AKT/NF-κB pathway.
• Inhibiting C5a-C5aR1 interaction improves RT sensitivity and anti-tumor effects.
• Combination therapy of RT and C5aR1 blockade offers a promising strategy for enhancing lung cancer treatment.