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Taxifolin Inhibits the Growth of Non-Small-Cell Lung Cancer via Downregulating Genes Displaying Novel and Robust
Xiaozeng Lin1,2,3, Ying Dong1,2,3, Yan Gu1,2,3
1Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada.
Abstract:
Using an LL2 cell-based syngeneic mouse LC model, taxifolin suppressed allografts along with the appearance of 578 differentially expressed genes (DEGs). These DEGs were associated with enhancement of processes related to the extracellular matrix and lymphocyte chemotaxis as well as the reduction in pathways relevant to cell proliferation. From these DEGs, we formulated 12-gene (TxflSig) and 7-gene (TxflSig1) panels; both predicted response to ICB (immune checkpoint blockade) therapy more effectively in non-small-cell lung cancer (NSCLC) than numerous well-established ICB biomarkers, including PD-L1. In both panels, the mouse counterparts of ITGAL, ITGAX, and TMEM119 genes were downregulated by taxifolin. They were strongly associated with immune suppression in LC, evidenced by their robust correlations with the major immunosuppressive cell types (MDSC, Treg, and macrophage) and multiple immune checkpoints in NSCLC and across multiple human cancer types. ITGAL, ITGAX, and IIT (ITGAL-ITGAX-TMEM119) effectively predicted NSCLC's response to ICB therapy; IIT stratified the mortality risk of NSCLC. The stromal expressions of ITGAL and ITGAX, together with tumor expression of TMEM119 in NSCLC, were demonstrated. Collectively, we report multiple novel ICB biomarkers-TxflSig, TxflSig1, IIT, ITGAL, and ITGAX-and taxifolin-derived attenuation of immunosuppressive activities in NSCLC, suggesting the inclusion of taxifolin in ICB therapies for NSCLC.
Insights
Taxifolin shows promise in treating non-small-cell lung cancer (NSCLC) by suppressing tumors and identifying novel biomarkers for immune checkpoint blockade (ICB) therapy response.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Non-small-cell lung cancer (NSCLC) remains a significant health challenge.
- Immune checkpoint blockade (ICB) therapy has revolutionized NSCLC treatment.
- Novel biomarkers are needed to predict ICB therapy response and improve patient outcomes.
Purpose of the Study:
- To investigate the effects of taxifolin on NSCLC growth and immune responses.
- To identify novel gene expression biomarkers for predicting ICB therapy response in NSCLC.
- To explore the potential of taxifolin as an adjunct therapy for NSCLC.
Main Methods:
- Utilized a syngeneic mouse model of lung cancer (LC) with LL2 cells.
- Analyzed differentially expressed genes (DEGs) following taxifolin treatment.
- Developed and validated gene panels (TxflSig, TxflSig1, IIT) for ICB response prediction.
Main Results:
- Taxifolin suppressed tumor allografts and altered gene expression related to extracellular matrix and lymphocyte chemotaxis.
- TxflSig and TxflSig1 panels demonstrated superior prediction of ICB response in NSCLC compared to PD-L1.
- Downregulation of ITGAL, ITGAX, and TMEM119 by taxifolin correlated with immune suppression and predicted ICB response and mortality risk.
Conclusions:
- Taxifolin attenuates immunosuppressive activities in NSCLC.
- Novel biomarkers including TxflSig, TxflSig1, and IIT (ITGAL-ITGAX-TMEM119) effectively predict ICB response and mortality risk in NSCLC.
- Taxifolin holds potential for inclusion in combination therapies for NSCLC.
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