Cutaneous leishmaniasis affects 1 million people worldwide annually. Although conventional treatments primarily target the parasite, there is growing interest in host immune modulation. In this study, we investigated the impact of synthetic β-carboline harmine (ACB1801), previously shown to be immunoregulatory in cancer, on the pathology caused by a drug-resistant Leishmania major strain causing persistent cutaneous lesions. Exposure to ACB1801 in vitro had a modest impact on parasite burden within host macrophages. Moreover, it significantly increased major histocompatibility complex II and costimulatory molecule expression on infected dendritic cells, suggesting an enhanced immune response. In vivo, ACB1801 monotherapy led to a substantial reduction in lesion development and parasite burden in infected C57BL/6 mice, comparable with efficacy of amphotericin B. Transcriptomics analysis further supported ACB1801 immunomodulatory effects, revealing an enrichment of TNF-α, IFN-γ, and major histocompatibility complex II antigen presentation signatures in the draining lymph nodes of treated mice. Flow cytometry analysis confirmed an increased frequency (1.5×) of protective CD4⁺IFN-γ⁺TNF-α⁺ T cells and a decreased frequency (2×) in suppressive IL-10⁺FoxP3^- T cells at the site of infection and in draining lymph nodes. In addition, ACB1801 downregulated the aryl hydrocarbon receptor signaling, known to enhance immunosuppressive cytokines. Thus, these results suggest a potential use for ACB1801 alone or in combination therapy for cutaneous leishmaniasis.

Frontiers in immunology

The β-carboline Harmine improves the therapeutic benefit of anti-PD1 in melanoma by increasing the MHC-I-dependent antigen presentation

Article

作者: Moer, Kris Van ; Karam, Manale ; Auclair, Christian ; Kumar, Akinchan ; Janji, Bassam ; Bosseler, Manon ; Noman, Muhammad Zaeem ; Berchem, Guy ; Bocci, Irene Adelaide

Harmine is a dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitor that displays a number of biological and pharmacological properties. Also referred to as ACB1801 molecule, we have previously reported that harmine increases the presentation of major histocompatibility complex (MHC)-I-dependent antigen on melanoma cells. Here, we show that ACB1801 upregulates the mRNA expression of several proteins of the MHC-I such as Transporter Associated with antigen Processing TAP1 and 2, Tapasin and Lmp2 (hereafter referred to as MHC-I signature) in melanoma cells. Treatment of mice bearing melanoma B16-F10 with ACB1801 inhibits the growth and weight of tumors and induces a profound modification of the tumor immune landscape. Strikingly, combining ACB1801 with anti-PD1 significantly improves its therapeutic benefit in B16-F10 melanoma-bearing mice. These results suggest that, by increasing the MHC-I, ACB1801 can be combined with anti-PD1/PD-L1 therapy to improve the survival benefit in cancer patients displaying a defect in MHC-I expression. This is further supported by data showing thati)high expression levels of TAP1, Tapasin and Lmp2 was observed in melanoma patients that respond to anti-PD1;ii)the survival is significantly improved in melanoma patients who express high MHC-I signature relative to those expressing low MHC-I signature; andiii)high expression of MHC-I signature in melanoma patients was correlated with increased expression of CD8 and NK cell markers and overexpression of proinflammatory chemokines involved in the recruitment of CD8+ T cells.

100 项与 ACB-1801 相关的药物交易

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