The total flavonoids of Hippophae rhamnoides stimulate recruitment of CD8+ T cells into the tumor microenvironment promoting cancer immune control

Abstract

Background: : Despite the immune checkpoint blocking therapy has changed the treatment of many cancers, most patients do not respond due to enhanced immunosuppression in the tumor microenvironment (TME). Hippophae rhamnoides Linn. (HR) is a widely concerned Edible Traditional Chinese medicine, it has been proved to have a certain immune-regulatory effect. Purpose: : In this study, we attempt to explore whether HR will provide a unique opportunity for immunotherapy. Method: : A systems pharmacology and RNA-seq analysis was used to reveal the potential mechanism of anti-tumor of HR. And we also used Western blot, real-time PCR, Flowcytometric analysis and other experimental techniques to verify the relevant mechanisms. Finally, the effects of combination regimens were examined in a non-small cell lung cancer (NSCLC) preclinical model. Results: : We demonstrate that the total flavonoids of HR (TFH) is the key for HR to play an anti-cancer role. TFH therapy activates the chemokine signaling pathway by downregulating the expression of chronic inflammatory factors, which results in increased CD8+T cells recruitment to the TME. In line with this, TFH enhanced the expression of related chemokines CCL5, XCL1, CXCL9/10, and induces a significant down-regulation of the negative regulatory factor prostaglandin E2 (PGE2). Ultimately, preclinical data suggest that TFH treatment in combination with anti-PD-1 blockade in inducing eradication of tumors. Conclusion: : TFH could be used as an effective adjuvant for immunotherapy of tumor patients.

Keywords

• Non-small cell lung cancer
• Chronic inflammatory factors
• Antitumor immunotherapy
• Systems pharmacology