Modified Bushen Yiqi formula enhances antitumor immunity by reducing the chemotactic recruitment of M2-TAMs and PMN-MDSCs in Lewis lung cancer-bearing mice

Abstract

Ethnopharmacological relevance: Modified Bushen Yiqi formula (MBYF) has shown efficacy as an herbal combination therapy with anti-PD-1 for lung cancer patients. However, the underlying mechanisms of its antitumor effects in lung cancer remain unclear.

Aim of the study: This study aims to observe the antitumor effect of MBYF and explore its synergistic mechanism in combination with anti-PD-1 based on the tumor immune microenvironment.

Materials and methods: The antitumor effect of MBYF was assessed in Lewis Lung Cancer (LLC)-bearing mice by evaluating tumor volume, weight, and histology in five groups (model control, MBYF 8.125 g/kg, MBYF 16.25 g/kg, MBYF 32.50 g/kg, anti-PD-1). Mechanisms were analyzed using pharmacology network and tumor RNA-sequencing. Tumor-infiltrating immune cells were measured by flow cytometry and immunohistochemistry. Targets and pathways were validated through qRT-PCR, immuno-histochemistry, and western blotting. The synergistic effect of MBYF in combination with anti-PD-1 was validated in three groups (model control, anti-PD-1, anti-PD-1+MBYF 16.25 g/kg).

Results: MBYF inhibited tumor growth and proliferation and demonstrated safety for the heart, liver, and kidney. Mechanistically, MBYF downregulated tumor proliferation by suppressing the expression of CCND1, CTNNB1, EGFR, and the PI3K-AKT/STAT3/ERK pathway. Furthermore, MBYF may upregulated the antitumor immunity (CD4+T cells, active CD8+ T cells, and NK cells) by reducing the infiltration of M2-TAMs and PMN-MDSCs. MBYF may inhibit the recruitment of M2-TAMs by downregulating the CCR5-CCLs axis and PMN-MDSCs by the CXCR2-CXCLs axis. In vivo study confirmed that MBYF enhanced the antitumor effect of anti-PD-1 therapy.

Conclusion: Modified Bushen Yiqi formula enhances antitumor immunity in the treatment of lung cancer by reducing the chemotactic recruitment of M2-TAMs and PMN-MDSCs, suggesting its potential as an adjunct therapy to enhance anti-PD-1 responses and improve treatment outcomes. Further research and clinical studies are needed to validate and expand upon these promising findings.

Keywords: Anti-PD-1; M2-TAMs; Modified bushen Yiqi formula; Non-small-cell lung cancer; PMN-MDSCs; Traditional Chinese medicine.