Enhancement of Th17-Inducing DC Vaccination for Ovarian Cancer Through PARPi-Mediated Activation of Innate Immunity in the Tumor Microenvironment
Abstract
This proposal seeks to address the hypothesis that PARP inhibitors enhance the efficacy of active immunotherapy with Th17-inducing DC vaccination against ovarian cancer. The proposed mechanism is that PARP inhibition will lead to DNA damage and innate immune sensing of cytosol DNA fragments, principally through the cGAS-STING pathway. We further propose that induction of deficiencies in homologous recombination (HR) will (i) sensitize ovarian tumors to PARP inhibitors, and (ii) trigger innate inflammation via DNA sensing and STING activation. In year 2 of this project, we have shown that treatment with prexasertib, a CHK1 inhibitor that promotes HR deficiency, triggers DNA damage, activates STING-related inflammatory pathways and alleviates tumor-associated immune suppression when combined with olaparib treatment. We further show that direct STING activation on ovarian tumor-associated macrophages alleviates macrophage-mediated suppression of antigen specific T cell responses. In vivo studies to test the therapeutic efficacy of Th17-DC vaccination combined with olaparib and agents that promote HR deficiency are in progress.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2022
- Accession Number
- AD1190703
Entities
People
- Martin J. Cannon
Organizations
- University of Arkansas for Medical Sciences