204P Maintenance of anti-tumour innate immune response in SCLC with DNA-PK inhibition

SCLC is a highly aggressive cancer that remains challenging to treat. Combining DNA damaging therapies (chemo-, radiotherapy or DNA damage repair inhibitors, DDRi) with immunotherapy (IO) can enhance the antitumor immune response by activating the stimulator of interferon genes (STING). However, only a small proportion of SCLCs, called "inflamed", benefit from immunotherapy, so there is a need for novel strategies to improve the immune response. We hypothesized that DDRi might sensitize immune resistant SCLC by simultaneously activating multiple innate immune pathways. RNA-seq data available in the cBio Cancer Genomics Portal were used to analyze STING1 mRNA expression in SCLC tumors (n=196 samples). DDR mRNA expression was assessed in n= 60 SCLC cell lines using the SclcCellMinerCDB database. SCLC patients derived PBMCs (n=10 samples) were whole exome sequenced for 58 DDR gene panels. These two models were used to assess the DNA-PK inhibition effect on immune mediated cytotoxicity and DNA/RNA sensors activation. High STING1-expressing SCLC tumours were characterized by increase of other innate immune pathways and DNA/RNA sensors (IFI-16, DDX60/DDX60L and MAVS activator RIG-I), as well as the effector kinases IRF1/7. RNAseq data also showed an inverse correlation between STING1 and DDR protein expression, suggesting that the dysregulation of the DDR system suppresses the innate immune mediated anti-tumour activity. Higher DDR expression of Non-Homologous End-Joining (NHEJ) components was observed in SCLC cell lines, as compared to other DDR pathways. In parallel, whole exome sequencing of PBMC samples from lung cancer patients was performed. Each subject had at least 1 germline alteration in a DDR gene. DNA-PK inhibitor (DNA-PKi) significantly increased the expression of STING and MAVS in SCLC cell lines and PBMCs. Increased mitochondrial recruitment of STING together with increased NK cell-mediated cytotoxicity was found in DNA-PKi treated immune cells. DNA-PKi also increased lymphocytes infiltration into tumour spheroids, resulting in tumour disruption. Collectively, our results elucidate a mechanism of anti-tumor immune response and support DNA-PKi as a novel therapeutic strategy to improve IO response in SCLC.