The Qi Yin San Liang San decoction enhances anti-CD19 CAR-T cell function in the treatment of B-cell lymphomas

Abstract

Ethnopharmacological relevanceAdoptive T-cell therapy with anti-CD19 chimeric antigen receptor (CAR)-expressing T cells is a new approach for treating advanced B-cell malignancies. However, CAR-Tcell therapies for tumors are challenging due to tumor heterogeneity, cytokine release syndrome (CRS), and CAR-T cell exhaustion. The Qi Yin San Liang San (SLS) decoction has a significant curative effect in treating tumors and can improve clinical efficacy when combined with tumor immunotherapy. However, there has been no in vitro or in vivo pharmacodynamic evaluation of SLS in combination with immunotherapy, and the underlying immunological mechanism remains unclear.Aim of the review: The study objective was to determine the auxiliary effect and potential mechanism of SLS as an adjuvant treatment with anti-CD19 CAR-T cells for B-cell lymphomas. Materials and methodsNetwork pharmacology analyses, in vitro and in vivo studies, and transcriptome sequencing analyses were performed. ResultsForty-two components were detected in SLS by HPLC. Sixteen pharmacologically active ingredients were analyzed by searching the TCMSP database. The predicted targets included IL-2, IL-6, IL-10, TNF-α, CASP7, and CASP9. In vitro studies revealed that SLS can dose-dependently promote the killing effect of unmodified T and anti-CD19 CAR-T cells against Raji cell lines. Meanwhile, SLS inhibited unmodified T and anti-CD19 CAR-T cell exhaustion, promoted anti-CD19 CAR-T cell proliferation, reduced the levels of IL-6, IL-10, and TNF-α, and increased granzyme B levels. In vivo studies, SLS effectively improved the anti-tumor function of anti-CD19 CAR-T cells, prolonged the survival of the mice, and reduced the levels of IL-6, GM-CSF, and IL-17. Subsequently, the transcriptomic analysis showed that SLS inhibited the IL-17 signaling pathway and the apoptosis signaling pathway of T cells. In addition, SLS downregulated the expression of IL-17A, IL-6, TNF-α, GM-CSF, S100A8, CASP 7, CASP 9, and CASP 10 in anti-CD19 CAR-T cells. SLS regulated the IL-17 signaling pathway and apoptosis signaling pathway in anti-CD19 CAR-T cells. ConclusionSLS plays a potential auxiliary role in enhancing the function of anti-CD19 CAR T cells in the treatment of B-cell lymphoma, improving the killing ability of these cells, reducing the potential risk associated with inflammation, and providing synergistic and attenuating effects. The mechanism of SLS is partially mediated by the apoptosis and IL-17 signaling pathways (such as IL-17A, IL-6, TNF-α, GM-CSF, and Granzyme B).