Targeting replication stress signaling to overcome immune evasion in small cell lung cancer

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New therapeutic strategies are urgently needed to improve immune checkpoint blockade (ICB) therapy in small cell lung cancer (SCLC). SCLCs rely heavily on the replication stress response (RSR) to mitigate oncogene- induced replication stress. Major RSR components are overexpressed in SCLC and are targets of small molecule inhibitors in clinical development. We demonstrated that RSR inhibition regulates PD-L1 expression, stimulates the cGAS/STING/TBK1 innate immune pathway to modulate immune responses in a type 1 interferon (T1IFN)- dependent fashion. We showed that targeting RSR with genetic or pharmacologic approaches is well-tolerated and potentiates the antitumor response with ICB in multiple mouse xenograft and genetic SCLC models. Our objective is to demonstrate that the novel direct link between RSR inhibition and immune sensing pathways can improve ICB efficacy in otherwise poorly immunogenic SCLCs. Our long-term goal is to develop novel immunotherapy approaches that can be readily translated into the clinic. Our overarching hypothesis is that RSR inhibition potentiates DNA damage while concurrently increasing PD-L1 expression and restoring antitumor immune responses through innate immune signaling activation and the resulting cytotoxic T-cell infiltration. In Aim 1, we will identify the cell-intrinsic effects of RSR inhibition on PD-L1 expression, post-translational modifications, and stabilization in SCLC by (1) defining the impact of RSR exacerbation on the AKT/GSK3β pathway; (2) identifying how RSR inhibition regulates PD-L1 expression, glycosylation, and stabilization in molecularly characterized human and genetically engineered mouse model (GEMM)-derived cell lines and in vivo models; and (3) investigating the effects of RSR inhibition on PD-L1 expression in SCLC patient samples and correlating with clinical outcomes. In Aim 2, we will determine the immunologic consequences of RSR inhibition on: (1) cGAS/STING-mediated innate immune pathway activation and the T1IFN response; (2) adaptive immunity and immune cell subsets in immunocompetent in vivo SCLC models; and (3) patient samples. In Aim 3, we will develop a therapeutic strategy combining RSR inhibitors with the current standard-of-care (anti- PD-L1+chemotherapy) in SCLC by (1) testing the antitumor efficacy of small molecule RSR inhibitors in combination with chemoimmunotherapy in autochthonous SCLC tumors in GEMMs; and (2) developing biomarkers that predict the therapeutic efficacy of RSR inhibition in combination with anti-PD-L1 and chemotherapy. In this aim we will dissect the immune changes, at a single cell resolution. I have a track record of productivity in studying SCLC and RS biology and have assembled a multidisciplinary team with expertise in immunology, single-cell technologies, bioinformatics, and mouse models. The proposed research will define a new connection between RSR signaling, PD-L1 expression, and innate immunity. The results will outline a novel therapeutic opportunity to use RSR inhibitors to rescue the efficacy of ICB in SCLC, the most aggressive form of lung cancer, which is highly relevant to the mission of the NCI.