Eliminating Radiation Resistance of Non-Small Cell Lung Cancer by Dihydroartemisinin Through Abrogating Immunity Escaping and Promoting Radiation Sensitivity by Inhibiting PD-L1 Expression

Abstract

Radiation resistance is linked to immune escaping and radiation sensitivity. In this study, we found that the PD-L1 expressions of non-killed tumor cells in NSCLC were enhanced after radiotherapy, and dihydroartemisinin (DHA) could synergistically enhance the antitumor effect of radiotherapy in NSCLC. A total of 48 NSCLC patients with sufficient tumor tissues for further analyses were enrolled. The PD-L1 expressions of NSCLC were evaluated by immunohistochemistry. Cell apoptosis was measured by flow cytometry, and the relationship between the PD-L1 expression and radiation resistance was investigated in patient specimens, xenograft model, and cell lines. First, the results indicate that the PD-L1 expression of NSCLC was positively related with the radiation resistance. Second, we found that DHA could eliminate the radiation resistance and synergistically enhance the antitumor effect of radiotherapy in the NSCLC cells lines and xenograft model. Finally, mechanistically, DHA could inhibit the PD-L1 expression to avoid immune escaping by inhibiting TGF-b, PI3K/Akt, and STAT3 signaling pathways. In addition, DHA could activate TRIM21 and regulate the EMT-related proteins by inhibiting the PD-L1 so as to enhance the radiation sensitivity and eliminate radiation resistance to NSCLC. Collectively, this study established a basis for the rational design of integrated radiotherapy and DHA for the treatment of NSCLC.

Dihydroartemisinin: A Potential Drug for the Treatment of Malignancies and Inflammatory Diseases

“…Further, Zhang et al confirm that in NSCLC, on the one hand, DHA reduces the expression of PD-L1 on tumor cells by inhibiting the expression of TGF-b and PI3K/Akt and STAT3 signaling pathways, thus impairs tumor immune escape. On the other hand, DHA increases the sensitivity of NSCLC to radiotherapy by regulating the expression of EMT-associated proteins (79). In summary, DHA promotes T-cell-centered anti-tumor immunity by reducing the secretion of immunosuppressive cytokines and suppressing the number and function of immunosuppressive cells.…”

Malaria-associated secondary hemophagocytic lymphohistiocytosis: A case report

“…Artemisinin is mainly used in the treatment of malaria. Our patient was treated with artemether and dihydroartemisinin because the effect of dihydroartemisinin is 5 times more potent against malaria than artemisinin[ 3 ]. She subsequently took oral dihydroartemisinin and piperaquine phosphate.…”

Dihydroartemisinin broke immune evasion through YAP1/JAK1/STAT1, 3 pathways to enhance anti-PD-1 therapy in hepatocellular carcinoma

“…Our previous studies showed that DHA inhibited HepG2(Hao et al 2021) and HepG2215 cells (Shi et al 2019). Meanwhile, some studies suggested that DHA downregulated PD-L1 expression in non-small cell lung cancer (Zhang et al 2020). Interestingly, DHA decreased YAP1 in tumor tissues but increased YAP1 in para-tumor, leading to the increased ratio of YAP1, suggesting the competitive advantage of para-tumor tissues, which appears to eliminate liver tumor cells in mice (Moya et al 2019).…”

“…Dihydroartemisinin (DHA), approved by FDA as an anti-malarial drug, is a derivative of artemisinin extracted from artemisia annua . In addition, DHA inhibited the expression of PD-L1 by inhibiting TGF-β, STAT3 and PI3K/AKT signaling pathways in non-small cell lung cancer (Zhang et al 2020). Our previous study showed that DHA inhibited cell proliferation in human hepatocellular carcinoma HepG2215 cells (Shi et al 2019) and promoted p-STAT3 (Y705) nuclear localization in human tongue squamous cell carcinoma Cal-27 cells (Shi et al 2017).…”