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Tumor-Derived Complement C3 Overexpression in STK11-Mutant Lung Adenocarcinoma Drives Tumor Growth and Immune
Sora Suzuki1, Bojidar Kandar2, Catrina Ting2
1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Abstract:
Loss-of-function STK11 mutations occur in 15% to 20% of lung adenocarcinomas (LUAD) and correlate with immunotherapy failure and worse survival. By integrating analysis of human tumor samples, a human LUAD cell line panel, and Cancer Cell Line Encyclopedia and The Cancer Genome Atlas datasets, we found that C3 production was increased in human STK11-mutant versus STK11-wildtype (WT) LUAD, modulated by LKB1 loss, whereas high C3 expression in STK11-mutant LUAD was associated with worse survival. STK11 knockout (STK11-KO) in syngeneic murine LUAD tumors resulted in increased neutrophil and reduced T-cell infiltration and anti-PD-1 resistance. STK11-KO tumor growth was similar in C3-/- versus WT mice. In contrast, C3 deletion in STK11-KO tumors resulted in dramatic inhibition of tumor growth and enhanced sensitivity to anti-PD-1 in immunocompetent mice but had no significant effect in CD8-depleted WT mice or nude mice, pointing to tumor-derived C3 promoting immune evasion. Mechanistically, STK11 loss drove tumor-derived C3 production and downstream CXCL2 and complement factor H production that promoted immune evasion and impaired anti-PD-1 efficacy. Our results show a C3-driven signaling axis for STK11-mutant LUAD promoting immune evasion and identify therapeutic targets to render these tumors sensitive to anti-PD-1.
Insights
Loss-of-function STK11 mutations in lung adenocarcinoma (LUAD) increase C3 production, leading to immune evasion and resistance to anti-PD-1 therapy. Targeting this C3 axis may improve immunotherapy outcomes for LUAD patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Loss-of-function STK11 mutations are prevalent in lung adenocarcinoma (LUAD), associated with poor prognosis and immunotherapy resistance.
- Understanding the mechanisms behind STK11-mutant LUAD's immune evasion is critical for developing effective treatments.
Purpose of the Study:
- To investigate the role of C3 complement protein in STK11-mutant LUAD immune evasion and anti-PD-1 therapy resistance.
- To identify therapeutic targets within the C3-driven signaling axis in STK11-mutant LUAD.
Main Methods:
- Integrated analysis of human LUAD tumor samples, cell lines, CCLE, and TCGA datasets.
- Utilized STK11-knockout (KO) syngeneic murine LUAD models, including C3-deficient and immunocompromised mice.
- Assessed tumor infiltration, anti-PD-1 efficacy, and downstream molecular signaling (CXCL2, CFH).
Main Results:
- STK11-mutant LUAD exhibited increased C3 production, correlating with worse survival.
- STK11-KO LUAD tumors showed increased neutrophils, reduced T cells, and resistance to anti-PD-1 therapy.
- C3 deletion in STK11-KO tumors inhibited growth and sensitized to anti-PD-1 in immunocompetent mice, dependent on CD8+ T cells and C3.
- STK11 loss promoted tumor-derived C3, CXCL2, and CFH, contributing to immune evasion.
Conclusions:
- A C3-driven signaling axis promotes immune evasion in STK11-mutant LUAD.
- Targeting tumor-derived C3 offers a potential strategy to enhance anti-PD-1 efficacy in this LUAD subset.
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