Lairson, L. L. | Search bioRxiv

bioRxiv2023

Combination-Based Drug Screening for Induced Oligodendrocyte Differentiation Enables Mechanistic Insight and Identifies Optimal Drug Pairs for Remyelination

Remyelination-promoting agents have significant potential utility as therapies for the treatment of demyelinating diseases, including multiple sclerosis. Clemastine and bexarotene have recently been evaluated in Phase II clinical trials to evaluate their potential in this context, with evidence for drug-induced remyelination being observed in both trials. Efficacy levels for both agents as monotherapies, as well as dose-limiting toxicities, highlight the need for more effective approaches. Additionally, questions about the relevance of M1R as the target of clemastine, and also around a mechanism involving accumulation of 8,9-unsaturated sterols, remain. Here, we have identified potent alternatives to clemastine (i.e., doxepin and orphenadrine), which are predicted to have superior tolerability and efficacy profiles and provide mechanistic insight related to M1R, and have completed pairwise drug combination screens using diverse classes of OPC differentiation-inducing agents. Vitamin D receptor agonists were found to enhance M1R antagonist-induced OL differentiation. Select compounds implicated in 8,9-unsaturated sterol accumulation synergistically enhanced the activity of bexarotene in OPCs, which resulted in insights that implicate a critical role for liver-X-receptor in the mechanisms of both sterol-dependent and bexarotene-induced remyelination.

neuroscience↗

bioRxiv2022

Myeloid reprogramming by JAK inhibition enhances checkpoint blockade therapy

Unleashing anti-tumor T cell activity by checkpoint inhibition is effective in many cancer patients but clinical response rates remain limited. Myeloid derived suppressor cells erode antitumor lymphocyte numbers and function, and correlate with resistance to checkpoint inhibitors. By screening small molecule libraries, we identified JAK inhibitors ability to rescue T cell function. Despite its documented immune suppressive properties, the prototypical JAK inhibitor ruxolitinib enhanced the efficacy of immune checkpoint blockade in cancer. This effect correlated with loss of suppressive gene expression, and acquisition of immunostimulatory molecular markers and T cell stimulatory activity in myeloid cells. In preclinical models, ruxolitinib significantly improved the function and increased the total numbers of activated tumor-infiltrating NK and CD4 T cells compared to checkpoint blockade alone and the efficacy was conditional on granulocytic cells. In addition to myeloid reprogramming in the tumor, ruxolitinib blunts G-CSF signaling in the bone marrow to prevent expression of suppressive and chemotaxis genes in neutrophils. In a clinical trial of Hodgkin lymphoma patients resistant to checkpoint inhibitors, treatment with ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and levels of suppressive markers in myeloid cells but increased numbers of cytokine-producing T cells. These results support the therapeutic potential of JAK inhibition in combination with checkpoint inhibitors in cancer and highlight the potential of reshaped myeloid immunity to improve immunotherapy. One sentence summary: Ruxolitinib reshapes myeloid immunity to synergize with checkpoint inhibitors

immunology↗