A Type I Interferon Response Is Associated With Increased Mtor Activation In Idiopathic Multicentric Castleman Disease

Abstract Idiopathic multicentric Castleman disease (iMCD) is a deadly hematologic illness of unknown etiology involving episodic disease flares characterized by systemic inflammation and multiple organ system dysfunction. We previously showed that the mTOR signaling pathway is elevated in lymph nodes of iMCD patients and that an mTOR inhibitor is effective in preventing disease flares in a small cohort of patients. However, the upstream mechanisms and the cell types and mediators involved in disease pathogenesis remain unknown. Here, we developed a targeted approach to identify candidate cellular drivers and mechanisms in iMCD through flow cytometric and single-cell transcriptomic analysis. Using paired PBMC samples collected from ten iMCD patients during flare and later following resolution of flare (remission), we identified increased T cell activation and alterations in NK cell and monocyte subset frequencies during iMCD flare. These changes were associated with increased Type I Interferon (IFN-I) response gene signatures across CD8+ T cells, NK cells, and monocytes as well as mTOR signaling gene signatures within monocytes. Finally, we demonstrated that increased mTOR activation in iMCD may occur downstream of IFN-I signaling as we observed significantly greater induction of pS6, a readout of mTOR activation, in monocytes and T cells from iMCD remission samples compared to healthy donors. Importantly, this IFN-I-mediated mTOR activation can be abrogated through treatment with the JAKi, ruxolitinib. The data presented here corroborate the notion of widespread systemic inflammation during iMCD disease flare and suggest a role for hyperresponsiveness to IFN-I as a mechanistic driver of increased mTOR signaling in iMCD.