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Immune-independent acquired resistance to PD-L1 antibody initiated by PD-L1 upregulation via PI3K/AKT signaling can be reversed by anlotinib.

ABSTRACT: Despite the benefit with cancer immunotherapies in clinical implication, immunotherapeutic resistance occurred in many patients and the mechanism remains unknown. Increasing evidence has revealed that cell-intrinsic programmed cell death ligand 1 (PD-L1) may play a non-negotiable part in immunotherapeutic resistance. Our present study aimed to elucidate the immune-independent acquired resistance mechanism to PD-L1 antibody. We found elevated PD-L1 expression induced by PD-L1 antibodies in cancer cell and vascular endothelial cells (VECs) with substantially acquired resistance to PD-L1 antibodies. Moreover, proliferation of resistant cells was accelerated and the apoptosis was reduced in the absence of immune compared with parental cells. Subsequently, we confirmed that the activation of the PI3K/AKT pathway is involved in the upregulation of PD-L1 expression. Finally, we found that low dose of anlotinib downregulated PD-L1 expression only in VECs via inhibiting the PI3K/AKT pathway; however, the same effect was not observed in cancer cells. To sum up, our findings revealed that upregulation of PD-L1 via activation of the PI3K/AKT signal pathway may promote acquired resistance to PD-L1 antibodies in an immune-independent manner. SIGNIFICANCE: These findings provide new mechanisms of immunotherapeutic resistance and effective evidence of anlotinib combined with immunotherapy.

SUBMITTER: Gao Y

PROVIDER: S-EPMC10417303 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Immune-independent acquired resistance to PD-L1 antibody initiated by PD-L1 upregulation via PI3K/AKT signaling can be reversed by anlotinib.

Gao Yuan Y Feng Yingfang Y Liu Shaochuan S Zhang Yan Y Wang Jing J Qin Tingting T Chen Peng P Li Kai K

Cancer medicine 20230623 14

Despite the benefit with cancer immunotherapies in clinical implication, immunotherapeutic resistance occurred in many patients and the mechanism remains unknown. Increasing evidence has revealed that cell-intrinsic programmed cell death ligand 1 (PD-L1) may play a non-negotiable part in immunotherapeutic resistance. Our present study aimed to elucidate the immune-independent acquired resistance mechanism to PD-L1 antibody. We found elevated PD-L1 expression induced by PD-L1 antibodies in cancer ...[more]

PMID: 37350549

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Project description:Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) has been implicated in the etiology of various human malignant tumors; however, its exact role in bladder cancer (BC) remains to be explored. Through reverse transcription‑quantitative PCR, western blotting and immunohistochemistry detection of BC tissue, combined with The Cancer Genome Atlas (TCGA) database analysis, the present study demonstrated that MTHFD2 was upregulated in BC tissues. MTHFD2 expression in patients with BC was frequently associated with worse prognosis, tumor immune cell infiltration and programmed death‑ligand 1 (PD‑L1) expression. Subsequently, using short hairpin RNA, the expression levels of MTHFD2 were knocked down in BC cell lines, and the results revealed that the tumor cell proliferation and colony formation abilities of cells were greatly reduced, as determined by Cell Counting Kit 8 and colony formation assays, as was the expression of PD‑L1, as determined by western blotting. These findings were also confirmed in a xenograft nude mouse model. Simultaneously, it was revealed that abnormal expression of MTHFD2 was closely associated with the PI3K/AKT signaling pathway in both RNA‑sequencing and TCGA datasets. This observation was verified in vitro by detecting the protein expression levels of PI3K and AKT by western blotting. The activation of PI3K and AKT was enhanced in BC cells (T24) following stimulation with 740Y‑P, a PI3K activator, and cellular activities and PD‑L1 expression levels were restored. Finally, it was demonstrated that the MTHFD2 levels were correlated with chemosensitivity to traditional BC chemotherapeutic agents and various PI3K/AKT‑targeted drugs, as determined by analyzing the Genomics of Drug Sensitivity in Cancer database. Overall, the present findings revealed that upregulation of MTHFD2 was associated with PD‑L1 activation in BC via the PI3K/AKT signaling pathway, suggesting that it could be a promising marker of chemotherapy and immunotherapy for BC.

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Dataset Information

Immune-independent acquired resistance to PD-L1 antibody initiated by PD-L1 upregulation via PI3K/AKT signaling can be reversed by anlotinib.

Publications

Immune-independent acquired resistance to PD-L1 antibody initiated by PD-L1 upregulation via PI3K/AKT signaling can be reversed by anlotinib.

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