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To test the effect of PARP targeting on response to ICB and the immune microenvironment, we treated an IC SCLC model andor antiPDL. Singleagent olaparib treatment had no significant antitumor activity, and consistent with the previous observation, anti PDL alone had no antitumor effect in these models. However, we observed striking tumor regressions in animals treated with the combination of olaparib and antiPDL.All animals had a complete tumor regression as early as day, and the effect was sustained until day. Thus, we tested a lower dose of olaparib and collected tumors from all treatment arms on day to determine changes in the immune microenvironment.In this experiment, we treated established RPP flank tumors in IC BF mice with olaparib for weeks. Representative images of staining intensity are shown.Following olaparib treatment, we again observed a significant increase in tumor PDL protein expression by RPPA analysis which was confirmed by immunoblot analysis. To investigate the effects of this combination in the endogenous lung microenvironment, we tested olaparib and anti PDL in the spontaneous RPP genetically engineered mouse model mode of SCLC.As expected from prior experience with this model, we observed appreciable tumor burden at this time by analysis of hematoxylin and eosin. The mice were randomized into groups based on their baseline tumor burden to ensure comparable tumor burdens between treatment groups.We further performed an immunoblot analysis of tumor lysates resected from the lungs for a panel of apoptosis markers to investigate tumor cell killing in the animals treated with the combination regimen.In agreement with the changes in tumor volume, we observed no appreciable change in cleaved caspase or after olaparib or antiPDL singleagent treatments. However, there was a noticeable increase in the expression of cleaved caspase and in the tumors treated with the combination of olaparib and antiPDL, thus confirming tumor cell killing with this treatment. Moreover, olaparib treatment appreciably increased PDL protein expression compared with vehicletreated animals. However, we observed a significantly higher CD staining intensity and percentage of CD cells in antiPDL olaparibtreated group. SC and SD to see whether consistent changes were induced versus the endogenous lung tumors.To further confirm that the synergistic antitumor effect of combined DDRPDL targeting is not modelspecific, we investigated the effect of this combination in additional SCLC models.For this, we selected an additional RPP model doubleknockout RP model tumorbearing mice with prexasertib with or without antiPDL. As expected, antiPDL had no antitumor benefit in either the KP or KP model. Singleagent prexasertib, however, showed significant delay in tumor growth in both models. Notably, in agreement with previous models, combined targeting of PDL and either CHK or PARP led to remarkable antitumor effect in these models.In KP, by day, we observed complete tumor regression in of animals when treated with prexasertib antiPDL antibody, and complete regression in of animals when treated with olaparib antiPDL antibody.In KP, by day, we observed complete tumor regression in of animals when treated with prexasertib antiPDL antibody and complete regression in of animals when treated with olaparib antiPDL antibody.These observations clearly demonstrated that the synergistic antitumor benefit of combined DDR and PDL blockade is not modelspecific in SCLC.

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