2. Academic Validation
  3. Icariside II potentiates the anti-PD-1 antitumor effect by reducing chemotactic infiltration of myeloid-derived suppressor cells into the tumor microenvironment via ROS-mediated inactivation of the SRC/ERK/STAT3 signaling pathways

Icariside II potentiates the anti-PD-1 antitumor effect by reducing chemotactic infiltration of myeloid-derived suppressor cells into the tumor microenvironment via ROS-mediated inactivation of the SRC/ERK/STAT3 signaling pathways

  • Phytomedicine. 2022 Dec 30;110:154638. doi: 10.1016/j.phymed.2022.154638.
Qing Kong 1,  Mengyu Ma 1,  Li Zhang 2,  Suqing Liu 3,  Shan He 3,  Jinfeng Wu 3,  Baojun Liu 4,  Jingcheng Dong 5
Affiliations

Affiliations

  • 1 Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institutes of Integrative Medicine, Fudan University, Shanghai, China.
  • 2 Department of Neurology, Huadong Hospital, Fudan University, Shanghai, China.
  • 3 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
  • 4 Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institutes of Integrative Medicine, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 5 Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institutes of Integrative Medicine, Fudan University, Shanghai, China. Electronic address: [email protected].
PMID: 36621167 DOI: 10.1016/j.phymed.2022.154638
Abstract

Background: Immune checkpoint blockade agents, such as anti-PD-1 Antibodies, show promising antitumor efficacy but only a limited response in patients with non-small cell lung Cancer (NSCLC). Icariside II (IS), a metabolite of Herba Epimedii, is a COX-2 and EGFR inhibitor that can enhance the anti-PD-1 effect. This study aimed to evaluate the antitumor effect of IS in combination with anti-PD-1 and explore the underlying mechanism.

Methods: Tumor growth was assessed in Lewis Lung Cancer (LLC) tumor-bearing mice in seven groups (control, IS 20 mg/kg, IS 40 mg/kg, anti-PD-1, IS 20 mg/kg+anti-PD-1, IS 40 mg/kg+anti-PD-1, ERK inhibitor+anti-PD-1). Tumor-infiltrating immune cells were measured by flow cytometry. The mechanisms were explored by tumor RNA-seq and validated in LLC cells through molecular biological experiments using qRT‒PCR, ELISA, and western blotting.

Results: Animal experiments showed that IS in combination with anti-PD-1 further inhibited tumor growth and remarkably reduced the infiltration of myeloid-derived suppressor cells (MDSCs) into the tumor compared with anti-PD-1 monotherapy. RNA-seq and in vitro experiments showed that IS suppressed the chemotactic migration of MDSCs by downregulating the expression of CXC chemokine ligands 2 (CXCL2) and CXCL3. Moreover, IS promoted Reactive Oxygen Species (ROS) generation and inhibited the activation of Src/ERK/STAT3 in LLC cells, which are upstream signaling pathways of these chemokines.

Conclusion: IS potentiates the anti-PD-1 anti-tumor effect by reducing chemotactic infiltration of the myeloid-derived suppressor cell into the tumor microenvironment, via ROS-mediated inactivation of Src/ERK/STAT3 signaling pathways.

Keywords

Anti-PD-1; CXCL2 and CXCL3; Icariside II; Myeloid-derived suppressor cells; Non-small-cell lung carcinoma; ROS-mediated SRC/ERK/STAT3 signaling pathways.

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