| Popis: |
Despite the availability of numerous new therapies including immune checkpoint inhibitors, patients with colon cancer are faced with limited treatment options. We recently demonstrated that low metronomic dose of PARP inhibitor synergizes with anti-PD-1 immunotherapy, in part, by modulating the suppressive function of MDSCs via a reduction in Arg1 and iNOS but independently of DNA damage and STING (PMC7839867). The non-antibiotic properties of minocycline (Mc) include its ability to moderately inhibit PARP. We took advantage of Mc as a weak PARP inhibitor to explore its potential on tumorigenesis and immune suppression in colon cancer models. In this study, we show that Mc significantly reduced Arg1 and iNOS in bone marrow (BM)-derived MDSCs both at the mRNA and protein levels. Paradoxically, such strong effect did not culminate in a substantial modulation of MDSCs suppressive function as assessed by co-cultured anti-CD3/CD28-stimulated CFSE-labeled T cells proliferation. However and similarly to PARP inhibitors, Mc increased PD-L1 expression in several cell types. We thus speculated that the antibiotic might enhance anti-cancer immunotherapy and explored such potential in a MC-38 and CT-26 cell-based mouse models of colon cancer representing the MSI and MSS traits of the disease. Treatment of tumor-bearing mice with low metronomic doses of Mc (0.5 or 5mkg) promoted a substantial reduction in tumor size in the MC-38 cell-based model (MSI) without an apparent superiority of any of the two doses. Surprisingly, neither dose of Mc exerted appreciable effects on tumor size in the CT-26 cell-based model (MSS). The anti-tumor effect of Mc in the MSI model was associated with a significant reduction in intratumoral monocytic-MDSC population. While MDSCs harvested from tumors of control mice re-infiltrated ex vivo generated MC-38 cell-based organoids, MDSCs harvested from tumors of Mc-treated mice failed to re-infiltrate the organoids. This suggests that Mc may interfere with MDSCs intratumorally infiltration. The Mc concentrations used in this study exerted little to no effect on bacterial growth suggesting that the observed effects were independent of the antibiotic properties of the drug. Unlike the effects observed in vitro, Mc treatment reduced intratumoral PD-L1 while increasing IFNγ. The discrepancy may be associated with intratumoral stress condition as assessed by Chop protein levels and reproduced in vitro by serum starvation. Although the metronomic Mc dose and anti-PD1 administration caused a significant reduction in tumor size individually, the combination therapy promoted a 66.7% curing of the tumors. Our results propose repurposing Mc at metronomic doses as a new approach to enhance efficacy of immunotherapy for patients with MSI colon cancer. Citation Format: Salome V. Ibba, Hanh H. Luu, Mohamed Ghonim, Cecilia Vittori, Matthew J. Dean, Giulia Monticone, Francesca Peruzzi, Augusto Ochoa, Lucio Miele, Hamid A. Boulares. Minocycline-based metronomic therapy as a novel approach to enhance anti-tumor immune responses and reduce tumor burden in mouse models of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4211. |
