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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.

SUBMITTER: Zhang M

PROVIDER: S-EPMC9247850 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Lung cancer is the most prevalent in cancer-related deaths, while breast carcinoma is the second most dominant cancer in women, accounting for the most number of deaths worldwide. Cancers are heterogeneous diseases that consist of several subtypes based on the presence or absence of hormone receptors and human epidermal growth factor receptor 2. Several drugs have been developed targeting cancer biomarkers; nonetheless, their efficiency are not adequate due to the high reemergence rate of cancers and fundamental or acquired resistance toward such drugs, which leads to partial therapeutic possibilities. Recent studies on cardiac glycosides (CGs) positioned them as potent cytotoxic agents that target multiple pathways to initiate apoptosis and autophagic cell death in many cancers. In the present study, our aim is to identify the anticancer activity of a naturally available CG (strophanthidin) in human breast (MCF-7), lung (A549), and liver cancer (HepG2) cells. Our results demonstrate a dose-dependent cytotoxic effect of strophanthidin in MCF-7, A549, and HepG2 cells, which was further supported by DNA damage on drug treatment. Strophanthidin arrested the cell cycle at the G2/M phase; this effect was further validated by checking the inhibited expressions of checkpoint and cyclin-dependent kinases in strophanthidin-induced cells. Moreover, strophanthidin inhibited the expression of several key proteins such as MEK1, PI3K, AKT, mTOR, Gsk3α, and β-catenin from MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling. The current study adequately exhibits the role of strophanthidin in modulating the expression of various key proteins involved in cell cycle arrest, apoptosis, and autophagic cell death. Our in silico studies revealed that strophanthidin can interact with several key proteins from various pathways. Taken together, this study demonstrates the viability of strophanthidin as a promising anticancer agent, which may serve as a new anticancer drug.

Project description:BackgroundPancreatic cancer is one of the most aggressive and intractable malignant tumors, and most deaths from pancreatic cancer are related to metastases. It has been demonstrated in vitro that overexpression of programmed death-ligand 1 (PD-L1) correlates with a lack of phosphatase and tensin homologue (PTEN) expression in pancreatic cancer tissue. This loss of PTEN expression may aberrantly activate the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and thereby promote tumor cell survival, proliferation, and disease progression. In this study, we investigated the potential therapeutic effect of blockading PD-L1 expression on the progression of pancreatic cancer and its spontaneous liver metastases in vivo by inhibiting the PI3K/Akt/mTOR signaling pathway.MethodsWe investigated the effect of blockading PD-L1 in an orthotopic pancreatic cancer mouse model. The pancreatic tumor weights and inhibition ratios were determined after treatment with antimouse PD-L1 antibody for 5 weeks. We used immunohistochemistry methods to investigate PD-L1 expression in pancreatic cancer tissue and spontaneous liver metastasis tissue. The levels of mRNA and protein expression for various components involved in the PI3K/Akt/mTOR signaling pathway as well as for matrix metalloproteinases-2 and -9 (MMP2 and MMP9) were measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blot methods, respectively.ResultsBlockading PD-L1 significantly inhibited tumor growth and decreased the levels of PD-L1 expression in tumor tissue. Furthermore, the levels of PTEN mRNA and protein expression were elevated, while the levels of phospho-Akt (p-Akt) and phospho-mTOR (p-mTOR) protein were decreased in pancreatic cancer and liver metastasis tissues after establishing a PD-L1 blockade. In addition, a PD-L1 blockade decreased the levels of MMP2 and MMP9 mRNA and protein expression in tumor tissues.ConclusionOur results suggest that a blockade of PD-L1 may inhibit the growth and metastasis of pancreatic cancer by modulating the PI3K/Akt/mTOR pathway.

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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.

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