| First Author | Cruz Cruz J | Year | 2023 |
| Journal | Front Immunol | Volume | 14 |
| Pages | 1146721 | PubMed ID | 36960055 |
| Mgi Jnum | J:334966 | Mgi Id | MGI:7447635 |
| Doi | 10.3389/fimmu.2023.1146721 | Citation | Cruz Cruz J, et al. (2023) Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment. Front Immunol 14:1146721 |
| abstractText | BACKGROUND: Previous studies show that the spleen and bone marrow can serve as leukemia microenvironments in which macrophages play a significant role in immune evasion and chemoresistance. We hypothesized that the macrophage driven tolerogenic process of efferocytosis is a major contributor to the immunosuppressive leukemia microenvironment and that this was driven by aberrant phosphatidylserine expression from cell turnover and cell membrane dysregulation. METHODS: Since MerTK is the prototypic efferocytosis receptor, we assessed whether the MerTK inhibitor MRX2843, which is currently in clinical trials, would reverse immune evasion and enhance immune-mediated clearance of leukemia cells. RESULTS: We found that inhibition of MerTK decreased leukemia-associated macrophage expression of M2 markers PD-L1, PD-L2, Tim-3, CD163 and Arginase-1 compared to vehicle-treated controls. Additionally, MerTK inhibition led to M1 macrophage repolarization including elevated CD86 and HLA-DR expression, and increased production of T cell activating cytokines, including IFN-beta, IL-18, and IL-1beta through activation of NF-kappaB. Collectively, this macrophage repolarization had downstream effects on T cells within the leukemia microenvironment, including decreased PD-1(+)Tim-3(+) and LAG3(+) checkpoint expression, and increased CD69(+)CD107a(+) expression. DISCUSSION: These results demonstrate that MerTK inhibition using MRX2843 altered the leukemia microenvironment from tumor-permissive toward immune responsiveness to leukemia and culminated in improved immune-mediated clearance of AML. |
