Transcriptomic mechanisms underlying the immune modulating function and therapeutic efficacy of PARP inhibitors

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Transcriptomic mechanisms underlying the immune modulating function and therapeutic efficacy of PARP inhibitors Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are approved for the treatment of ovarian cancer, as well as BRCA1 or BRCA2 (BRCA1/2) mutant breast and pancreatic cancers. Our current understanding is that one of the main mechanisms responsible for the efficacy of PARPis is through synthetic lethality, specifically in cancers with homologous recombination repair defects (‘BRCAness’). While PARP1-mediated PARylation is an essential regulator of gene transcription, it remains unknown how PARPi-induced transcriptomic changes contribute to its therapeutic efficacy. While our preclinical and clinical studies assessing PARPis in combination with programmed cell death-ligand 1 (PD-L1)/PD-1 inhibitors (PD-1/L1is) showed durable responses in different cancers, the responses were heterogeneous between patients, and surprisingly, the therapeutic benefit of this combination did not correlate with known predictive biomarkers for PARPis, such as BRCA1/2 mutations. These data suggest that the immunomodulating function of PARPis may be different from or independent of the existing ‘BRCAness’ paradigm underlying the therapeutic efficacy of PARPis. To determine the molecular mechanisms underlying the immunomodulating function of PARPis, we utilized single-cell RNA sequencing to assess the transcriptomic impact of PARPis on tumor cells and the tumor immune microenvironment. Surprisingly, we identified that PARPi-induced PARP1-trapping to DNA may upregulate B7-H3 (CD276), a key immune checkpoint protein. Based on our preliminary studies, we hypothesize that PARPis transcriptionally regulate cancer-cell intrinsic B7-H3 expression by trapping the PARP1 protein to the B7-H3 promoter region, which may serve as a key regulatory node for the immunomodulating function and therapeutic efficacy of PARPis. We will use cell and animal models, as well as patient specimens from clinical trials of PARPi-based therapies to test this hypothesis. We will test three aims: Aim 1: Determine mechanisms by which PARPis transcriptionally induce cancer cell intrinsic B7-H3 expression through PARP1-chromatin trapping. Aim 2: Determine if B7-H3 functions as a key regulatory node for the immunomodulating function and efficacy of PARPis in preclinical animal models. Aim 3: Validate PARPi-induced B7-H3 expression as a biomarker in determining the efficacy of PARPis as immunomodulating agents by analysing patient tumor and blood samples from multiple clinical trials. We believe that our proposal is highly innovative because it fills key gaps in our knowledge of the therapeutic efficacy of PARPis as immunomodulating agents through transcriptional regulation, which goes beyond the current mechanistic paradigm of PARPis. If successful, our study will have a significant impact on expanding the clinical applications of PARPis as immunomodulating agents by promoting antitumor immunity and enhancing the efficacy of immunotherapy. This may also lead to the clinical development of rational PARPi combinations with an B7-H3 inhibitor and/or a PD-1/L1i, depending on the immune characteristics of the individual patient tumor.