ABSTRACT
The majority of metastatic, castrate-resistant prostate cancer (mCRPC) patients are de novo resistant to immune checkpoint blockade (ICB), so therapeutic strategies to enhance immune-responsiveness are urgently needed. Here we performed a co-clinical trial of PARP inhibitor (PARPi) in combination with PD-1 or PDL-1 antibody in genomically unselected mCRPC patients or homologous-recombination proficient murine models, respectively, which demonstrated lack of efficacy. In contrast, PARPi in combination with PI3K inhibitor (PI3Ki), induced tumor regression via macrophage STING-dependent innate immune activation in vivo, and enhanced T-cell infiltration/activation in c-myc driven murine prostate cancer models, which was augmented by PD-L1 blockade. Ex vivo mechanistic studies revealed that PARPi-induced DNA double strand break-associated microvesicles released from tumor cells, coupled with PI3Ki-mediated c-GAS de-repression, were both required for macrophage cGAS/STING pathway activation. These data demonstrate that PARPi/PI3Ki combination triggers macrophage STING-mediated anti-cancer innate immunity, which is sufficient to induce tumor regression in ICB-refractory c-myc-driven prostate cancer.
STATEMENT OF SIGNIFICANCE Co-targeting of PARP and PI3K signaling pathways activates c-GAS/STING pathway within tumor-associated macrophages, thereby enhancing T cell recruitment/activation and cancer clearance in c-myc-driven murine prostate cancer models. PARPi/PI3Ki combination therapy could markedly increase the fraction of mCRPC patients responsive to ICB, independent of germline or tumor homologous recombination status.
Competing Interest Statement
Dr. Patnaik has received research support from Bristol Myers Squibb. In addition, Drs. Patnaik and Stadler have received clinical trial funding support from both Clovis Oncology and Bristol Myers Squibb.
Footnotes
FINANCIAL SUPPORT: Dr. Patnaik has received research support from Bristol Myers Squibb. In addition, Drs. Patnaik and Stadler have received clinical trial funding support from both Clovis Oncology and Bristol Myers Squibb.
CONFLICT OF INTEREST: As noted above for Financial Support.