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

Autor:	Ghonim MA; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Ibba SV; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Tarhuni AF; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Errami Y; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Luu HH; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Dean MJ; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., El-Bahrawy AH; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Wyczechowska D; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Benslimane IA; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Del Valle L; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Al-Khami AA; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Ochoa AC; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Boulares AH; Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA hboulr@lsuhsc.edu.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2021 Jan; Vol. 9 (1).
DOI:	10.1136/jitc-2020-001643
Abstrakt:	Background: Poly(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. Methods: Colon 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 APC Min/+ 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, MSI high ) 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. Results: Partial PARP-1 inhibition, via gene heterozygosity or a moderate dose of olaparib, protected against colitis-mediated/ APC Min -mediated intestinal tumorigenesis and APC Min -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 MSI high or reduction of MSS tumors in mice. Conclusions: These 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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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