PARP inhibitor radiosensitization enhances anti-PD-L1 immunotherapy through depression of chemokine translation in small cell lung cancer
Immunotherapy (IO) is an effective therapeutic for various cancers however the benefits are modest for small cell lung cancer (SCLC). The poor response of SCLC to anti-PD-1/PD-L1 IO is due in part to the lack of cytotoxic T cells because of limited chemokine expression from SCLC tumors. Immunogenic radiosensitizers that enhance chemokine expression may be a promising strategy forward. Here, we showed that the PARP inhibitor, olaparib, in combination with radiotherapy (RT) enhanced immune activation and anti-tumor efficacy in SCLC cell lines, patient-derived xenograft (PDX) and syngeneic mouse models, that was further pronounced with continued delivery of adjuvant olaparib. The combination treatment (olaparib with RT) activated the cGAS-STING pathway and increased the mRNA levels of the T cell chemoattractants, CCL5 and CXCL10. Interestingly, we found the combination treatment significantly downregulated expression of the mRNA translational repressor EIF4E2 to further increase chemokine CXCL10 protein levels via post-transcriptional stabilization of CXCL10 mRNA in its 3' UTR region. We demonstrated the combination treatment augmented cytotoxic CD8+ T cell tumor infiltration and upregulated PD-L1 gene expression and protein levels. The incorporation of anti-PD-L1 IO with olaparib and RT significantly improved anti-tumor efficacy by protecting T cells from exhaustion. This study identified a novel mechanism of treatment-induced chemokine regulation that provides a rationale for the combination of PARP inhibitors, RT and anti-PD-L1 IO as a novel treatment strategy for SCLC. Overall design: To investigate the gene expressions modulated by the olaparib combined with radiation, we treated SBC5 cells with vehicle (DMSO), olaparib (1uM), radiation (4Gy) or the combination (olaparib+radiation) for 3 days. We then performed  gene expression profiling analysis using data obtained from RNA-sequencing from cells under four conditions. Comparative gene profiling analysis of RNA-seq data for combination (PARPi+4Gy) vs Vehicle (DMSO+0Gy), RT (DMSO+4Gy) vs Vehicle (DMSO+0Gy) and PARPi (PARPi+0Gy) vs Vehicle (DMSO+0Gy).