Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors

Abstract

Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy such as anti-PD-L1 antibody in treating cancers, myeloid-derived suppressor cells (MDSCs) that lead to the formation of the protumor immunosuppressive microenvironment are one of the major contributors to ICB resistance. Therefore, inhibition of MDSC accumulation and function is critical for further enhancing the therapeutic efficacy of anti-PD-L1 antibody in a majority of cancer patients. Artemisinin (ART), the most effective antimalarial drug with tumoricidal and immunoregulatory activities, is a potential option for cancer treatment. Although ART is reported to reduce MDSC levels in 4T1 breast tumor model and improve the therapeutic efficacy of anti-PD-L1 antibody in T cell lymphoma-bearing mice, how ART influences MDSC accumulation, function, and molecular pathways as well as MDSC-mediated anti-PD-L1 resistance in melanoma or liver tumors remains unknown. Here, we reported that ART blocks the accumulation and function of MDSCs by polarizing M2-like tumor-promoting phenotype towards M1-like antitumor one. This switch is regulated via PI3K/AKT, mTOR, and MAPK signaling pathways. Targeting MDSCs by ART could significantly reduce tumor growth in various mouse models. More importantly, the ART therapy remarkably enhanced the efficacy of anti-PD-L1 immunotherapy in tumor-bearing mice through promoting antitumor T cell infiltration and proliferation. These findings indicate that ART controls the functional polarization of MDSCs and targeting MDSCs by ART provides a novel therapeutic strategy to enhance anti-PD-L1 cancer immunotherapy.

Ginseng Glucosyl Oleanolate from Ginsenoside Ro, Exhibited Anti-Liver Cancer Activities via MAPKs and Gut Microbiota In Vitro/Vivo

“…Ginsenoside Rk1 can also inhibit the proliferation of lung cancer cells by suppressing the expression of PD-L1 . Additionally, artemisinin has been reported to augment the efficacy of PD-L1 immunotherapy for liver cancer through the MAPK signaling pathway . Similarly, we demonstrated that PD-L1 expression was inhibited after the addition of GGO, highlighting the potential of GGO as an immune suppressor and providing direction for future research.…”

Emerging predictive biomarkers for novel therapeutics in peripheral T-cell and natural killer/T-cell lymphoma

“…Epigenetic modifiers such as HDAC inhibitors have thus been identified to promote sensitization of tumor cells to PD-1/PD-L1 immune checkpoint inhibitors via reversal of MDSC’s immunosuppressive effect on the cancer milieu, demonstrating synergistic effects with immunotherapeutic options in solid tumors ( 212 ). We observe further agents such as artemisinin used in MDSC suppression, which improved the efficacy of anti-PD-L1 blockade therapy in mice with T cell lymphoma ( 213 ). The presence of a deficiency in the MDSC-polarizing TIPE2 gene additionally informed of MDSC activity and thus delayed tumor progression in mice ( 214 ).…”

Plant-derived natural products and combination therapy in liver cancer

“…Ginsenoside-Rg3 inhibited cell proliferation and invasion of SMMC-7721 cells through PI3K/AKT pathway, which effectively decreased the levels of phosphorylated (p)-AKT, p-PI3K, MMP2, MMP9 and long non-coding RNA HOX antisense intergenic (lncRNA HOTAIR) (40). Recently, Zhang et al showed that artemisinin enhanced the effect of anti-programmed cell death-ligand 1 (anti-PD-L1) immunotherapy by blocking the accumulation and function of myeloid-derived suppressor cells (MDSCs) via regulating PI3K/ AKT/mTOR and MAPK signaling pathways and polarizing M2-like pro-tumor phenotype to M1-like anti-tumor phenotype (41). Dihydroartemisinine inhibits proliferation and induces apoptosis of HepG2 cells through regulating Bcl-2/Bax/caspase-3 apoptosis signal pathway (42).…”

“…Recently, Zhang et al. showed that artemisinin enhanced the effect of anti-programmed cell death-ligand 1 (anti-PD-L1) immunotherapy by blocking the accumulation and function of myeloid-derived suppressor cells (MDSCs) via regulating PI3K/AKT/mTOR and MAPK signaling pathways and polarizing M2-like pro-tumor phenotype to M1-like anti-tumor phenotype ( 41 ). Dihydroartemisinine inhibits proliferation and induces apoptosis of HepG2 cells through regulating Bcl-2/Bax/caspase-3 apoptosis signal pathway ( 42 ).…”