Targeting PARP-1 with metronomic therapy modulates MDSC suppressive function and enhances anti-PD-1 immunotherapy in colon cancer

Abstract

BackgroundPoly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib) are effective against BRCA-mutated cancers at/near maximum tolerated doses by trapping PARP-1 on damaged chromatin, benefitting only small patient proportions. The benefits of targeting non-DNA repair aspects of PARP with metronomic doses remain unexplored.MethodsColon epithelial cells or mouse or human bone marrow (BM)-derived-myeloid-derived suppressor cells (MDSCs) were stimulated to assess the effect of partial PARP-1 inhibition on inflammatory gene expression or immune suppression. Mice treated with azoxymethane/four dextran-sulfate-sodium cycles or APCMin/+ mice bred into PARP-1+/− or treated with olaparib were used to examine the role of PARP-1 in colitis-induced or spontaneous colon cancer, respectively. Syngeneic MC-38 cell-based (microsatellite instability, MSIhigh) or CT-26 cell-based (microsatellite stable, MSS) tumor models were used to assess the effects of PARP inhibition on host responses and synergy with anti-Programmed cell Death protein (PD)-1 immunotherapy.ResultsPartial PARP-1 inhibition, via gene heterozygosity or a moderate dose of olaparib, protected against colitis-mediated/APCMin-mediated intestinal tumorigenesis and APCMin-associated cachexia, while extensive inhibition, via gene knockout or a high dose of olaparib, was ineffective or aggravating. A sub-IC50-olaparib dose or PARP-1 heterozygosity was sufficient to block tumorigenesis in a syngeneic colon cancer model by modulating the suppressive function, but not intratumoral migration or differentiation, of MDSCs, with concomitant increases in intratumoral T cell function and cytotoxicity, as assessed by granzyme-B/interferon-γ levels. Adoptive transfer of WT-BM-MDSCs abolished the protective effects of PARP-1 heterozygosity. The mechanism of MDSC modulation involved a reduction in arginase-1/inducible nitric oxide synthase/cyclo-oxygenase-2, but independent of PARP-1 trapping on chromatin. Although a high-concentration olaparib or the high-trapping PARP inhibitor, talazoparib, activated stimulator of interferon gene (STING) in BRCA-proficient cells and induced DNA damage, sub-IC50 concentrations of either drug failed to induce activation of the dsDNA break sensor. STING expression appeared dispensable for MDSC suppressive function and was not strictly required for olaparib-mediated effects. Ironically, STING activation blocked human and mouse MDSC function with no additive effects with olaparib. A metronomic dose of olaparib was highly synergistic with anti-PD-1-based immunotherapy, leading to eradication of MSIhigh or reduction of MSS tumors in mice.ConclusionsThese results support a paradigm-shifting concept that expands the utility of PARP inhibitor and encourage testing metronomic dosing of PARP inhibitor to enhance the efficacy of checkpoint inhibitor-based immunotherapies in cancer.

Exploring Immune-Related Prognostic Signatures in the Tumor Microenvironment of Colon Cancer

“…Immunotherapy takes advantage of the body’s own immune system to attack cancer, which has become a powerful and promising clinical strategy for treating various tumors ( Riley et al, 2019 ), including colon cancer( Chalabi et al, 2020 ; Lichtenstern et al, 2020 ; Ghonim et al, 2021 ). Immune checkpoint inhibitors (ICIs), a typical type of immunotherapy, function through inhibiting negative regulatory receptors, such as programmed cell death 1 ( PD-1 ) and cytotoxic T lymphocyte antigen 4 ( CTLA4 ), and thereby activates antitumor immunity ( Tolba, 2020 ).…”

Splenic Volume as a Surrogate Marker of Immune Checkpoint Inhibitor Efficacy in Metastatic Non Small Cell Lung Cancer

“…A high level of circulating MDSC at baseline is significantly associated with poor progression-free survival (PFS) and poor overall survival (OS) in mCRC and pancreatic cancer. High level of MDSC is also associated with resistance to ICI in preclinical models [ 12 , 13 ]. In a mouse model, splenomegaly was a surrogate marker of MDSC level and was associated with a poor prognosis [ 14 ].…”

Targeting Myeloid-Derived Suppressor Cells to Enhance the Antitumor Efficacy of Immune Checkpoint Blockade Therapy

“…Poly (ADP-ribose) polymerase inhibitors (PARPi) are also able to modulate MDSCs suppressive function involving a reduction in Arg-1/iNOS/COX-2. In preclinical colon cancer mouse models, Partial PARPi inhibition with metronomic therapy, such as olaparib and talazoparib, has been demonstrated to reactivate antitumor immunity through increases in intratumoral T-cell function and cytotoxicity, thus enhancing anti-PD-1 immunotherapy ( 106 ). Recent clinical trials with olaparib plus durvalumab, a human monoclonal antibody that targets PD-1, have also shown acceptable toxicity and improved patients’ outcome in metastatic castration-resistant prostate cancer (mCRPC) ( 107 ).…”