PARP inhibitor radiosensitization enhances anti-PD-L1 immunotherapy through depression of chemokine translation in small cell lung cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233820 | GEO | 2025/02/04

REPOSITORIES: GEO