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• W4387207935 abstract "Immunotherapy has modestly improved survival for small cell lung cancer (SCLC) patients. Low response rate and rapid disease progression remain an intractable challenge. One of the factors that contribute to immunotherapy resistance is the lack of cytotoxic T cell infiltration. The expression of chemoattractant cytokines, like CCL5 and CXCL10, are essential for T cell infiltration. The control of chemokine expression is not fully understood, but both transcriptional and translational control pathways could play a major role. Previous studies have shown a correlation between DNA damage and chemokine expression and that PARP inhibitors (PARPi) are radiosensitizers for SCLC that increases DNA damage. The objectives of this study were to define this potential PARPi immunogenic radiosensitizing relationship.We identified doses of olaparib+ radiation treatment (RT) that conferred radiosensitization in SCLC cell-lines by cell viability and/or clonogenic assays. Olaparib+RT induced CCL5 and CXCL10 mRNA expression was measured by qPCR across SCLC cell-lines. Protein level of chemokines was assessed by immunoblotting. SBC5 cells were treated with olaparib+RT and submitted for RNA sequencing analysis. Genes with adjusted p value<0.05 were considered significant. Protein level changes and target gene knock-out (KO) were confirmed by immunoblotting. Chemokine CXCL10 mRNA and protein level in wildtype (WT) and KO cells were measured by qPCR and western blot, respectively. A mRNA decay assay and dual-luciferase reporter assay was used to identify the region of CXCL10 mRNA that confers mRNA stability control. In vivo anti-tumor efficacy and tumor T cell infiltration studies were done in B6129F mice bearing KP1 tumors. And the T cell infiltration was measured by immune profiling.In vitro, olaparib+RT significantly increased CXCL10 mRNA in all four SCLC subtype cell-lines in comparison to vehicle control. Consistently, the increase of CXCL10 protein levels (3-fold) was observed in SBC5 cells. By RNA-Seq, a top-ranking translational repressor was EIF4E2 (4EHP) mRNA. The downregulation of EIF4E2 protein by olaparib+RT was validated in four SCLC subtypes by western blot. EIF4E2 KO in HEK293 and SBC5 cells increased CXCL10 mRNA and protein level. By mRNA decay assay and western blot, the absence of EIF4E2 stabilized CXCL10 mRNA and increased CXCL10 protein levels. The dual-luciferase assay demonstrated EIF4E2 destabilizes CXCL10 mRNA via the 3'UTR of CXCL10. In vivo, immune profiling showed olaparib+RT significantly increased the total T cell and CD8+ T cell infiltration. Finally, anti-PD-L1 inhibition potentiated olaparib + IR to improve tumor control in KP1 allograft.Our study demonstrated olaparib + RT increases CXCL10 protein levels through downregulating EIF4E2 to subsequently increase T cell infiltration. Olaparib + RT enhanced anti-PD-L1 immunotherapy efficacy and has therapeutic potential as an immunogenic radiosensitizer." @default.
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• W4387207935 date "2023-10-01" @default.
• W4387207935 modified "2023-10-17" @default.
• W4387207935 title "The Effect of PARP Inhibitor Radiosensitization on the mRNA Translational Regulation of T Cell Chemokines" @default.
• W4387207935 doi "https://doi.org/10.1016/j.ijrobp.2023.06.380" @default.
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