Abstract PR-03: Tumor-derived Complement Factor B drives tumor growth and anti-PD-1 resistance in <i>STK11</i>-mutant lung adenocarcinoma
Notice bibliographique
Résumé
Abstract Introduction: Loss-of-function STK11 mutations occur in 15-20% of lung adenocarcinomas (LUAD) and correlate with immunotherapy failure and poor outcomes. The complement pathway is a critical part of the innate immune response and we noted the upregulation of the central complement effector C3 in human STK11-mutant versus STK11-wild-type LUAD. High C3 mRNA expression in STK11-mutant LUAD was associated with worse survival in TCGA LUAD. We then developed a preclinical mouse model with Stk11 deletion (STK11-KO) in syngeneic murine CMT167 tumors (a spontaneous Kras G12V murine LUAD tumor model) resulting in increased neutrophil and reduced T cell infiltration and anti-PD-1 resistance similar to human STK11-mutant LUAD. 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 little effect following CD8 depletion or in nude mice, pointing to tumor-derived C3 promoting immune evasion. Comparison of gene expression in STK11KO and STK11KO-C3KO tumor showed that C3 modulates expression of multiple complement genes including complement Factor B (CFB), which is required for alternative complement pathway activation through the alternative pathway (AP) C3 and C5 convertases. We hypothesized that tumor-derived CFB promotes growth and anti-PD-1 resistance in STK11-mutant tumors. Methods: We used transient CRISPR-Cas9 RNP transfection to generate CMT167-STK11KO tumor cells with CFB deletion (CMT167-STK11KO-CFBKO) while avoiding the immunogenic effects of lentiviral based systems. We compared the subcutaneous tumor growth of CMT167-STK11KO-CFBKO and CMT167-STK11KO LUAD cells in immunocompetent mice to evaluate the effect of tumor-derived CFB in vivo. Iptacopan is an oral CFB inhibitor approved for paroxysmal nocturnal hemoglobinuria. We evaluated whether Iptacopan could overcome in-vivo anti-PD-1 resistance of CMT167-STK11KO tumors. Results: Knockout of CFB resulted in robust inhibition of STK11KO tumor growth in immunocompetent mice. Combination treatment with CFB inhibitor Iptacopan and anti-PD-1 reduced STK11KO tumor growth and extended survival of mice. Conclusions: Our results extend our prior findings of tumor-derived C3 promoting immune evasion in STK11-mutant LUAD and identify tumor-derived CFB in promoting tumor growth and immune check point inhibitor (ICI) resistance. These results identify tumor-derived C3 and CFB as a novel signaling axis within the innate immune system to target in STK11-mutant LUAD and point to the potential role of the alternative complement pathway in tumor immune evasion. These results also provide rationale for an early phase clinical trial of CFB inhibitors such as Iptacopan to enhance anti-PD-1 effectiveness in patients with STK11-mutant LUAD. Citation Format: Bojidar Kandar, Sora Suzuki, ANM Nazmul H. Khan, Peter Deraska, Thejaswini Giridharan, Han Yu, Brahm Segal, Edwin Yau. Tumor-derived Complement Factor B drives tumor growth and anti-PD-1 resistance in STK11-mutant lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr PR-03.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».