PARP inhibitor radiosensitization enhances anti-PD-L1 immunotherapy through stabilizing chemokine mRNA in small cell lung cancer

Abstract

Abstract Immunotherapy (IO) is an effective treatment 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 show that the PARP inhibitors (PARPi), including olaparib, talazoparib and veliparib, in combination with radiotherapy (RT) enhance the immune activation and anti-tumor efficacy in SCLC cell lines, patient-derived xenograft (PDX) and syngeneic mouse models. The effect is further enhanced by continued delivery of adjuvant PARPi. The combination treatment (PARPi with RT) activates the cGAS-STING pathway and increases the mRNA levels of the T cell chemo-attractants CCL5 and CXCL10. In addition to upregulation of transcription, the combination treatment increases chemokine CXCL10 protein levels via stabilization of CXCL10 mRNA in an EIF4E2-dependent manner. The incorporation of anti-PD-L1 IO into the PARPi with RT combination therapy further improves the anti-tumor efficacy by increasing T cell infiltration and function. This study thus provides a proof of principle for the combination of PARP inhibitors, RT and anti-PD-L1 IO as a treatment strategy for SCLC.