Multiomics Reveal Interferon-Induced Cell Senescence As a Novel Mechanism of Eculizumab Resistance in TA-TMA

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Background One third of patients still die from transplant associated thrombotic microangiopathy (TA-TMA) despite prompt treatment with eculizumab. We hypothesize that cellular and soluble complement modifiers contribute to eculizumab resistance in TA-TMA and knowledge of these mechanisms may guide novel biomarkers and therapies. Objectives We sought to perform a multiomic analysis of TA-TMA patient samples to determine mechanisms of eculizumab resistance. Methods A pharmacokinetic (PK)/pharmacodynamic (PD) analysis of eculizumab levels and sC5b-9 in 60 TA-TMA patients was performed to identify eculizumab responders and non-responders (described in Abstract #28077). Peripheral blood mononuclear cells (PBMCs) from responders (n=4) and non-responders (n=4) underwent single cell RNAseq at 2 timepoints: 1) TA-TMA diagnosis (prior to eculizumab initiation) and 2) at the time of eculizumab “escape” in non-responders (or matched timepoint in responders). Plasma from the same patients and timepoints underwent proteomic analysis (Somascan 11k). Results Non-classical monocytes (NCMs) were markedly different in responders and non-responders at diagnosis (Fig.1) and eculizumab escape (Fig.2). Non-responder NCMs at TA-TMA diagnosis were enriched for interferon alpha/beta (p=7.3e-9) and interferon signaling (p=3.9e-5). This aligned with the plasma proteome at TA-TMA diagnosis, which was enriched for interferon signaling (p=1.5e-3) and interferon alpha/beta signaling (p=7.9e-3) in non-responders. NCMs were also enriched for DNA damage/telomere stress induced senescence (p=2.8e-9), senescence-associated secretory phenotype (p=3e-4) and oxidative stress induced senescence (p=4.3e-3). Cell senescence is induced by interferons and impedes the crucial role of NCMs in vascular maintenance and repair. The role of senescence in TA-TMA is also seen at the time of eculizumab escape. NCMs in non-responders showed inhibited eukaryotic translation elongation (p=2.9e-33), EIF2 signaling (p=1.5e-30), eukaryotic translation initiation (p=1.6e-27) and RNA processing pathways (p=2.2e-25). These pathways are crucial for normal protein synthesis, and the strong inhibitory signal supports ongoing cell dysfunction from interferon-induced senescence. The plasma proteome at the time of eculizumab escape was also enriched for DNA damage/telomere stress induced senescence (p=4.6e-6), senescence pathway (p=8.8e-5) and senescence-associated secretory phenotype (p=3.1e-4) in non-responders. Conclusions We performed the first PK/PD guided multiomics analysis of PBMCs and plasma from eculizumab responders and non-responders. This study identified the novel role of interferon-induced cell senescence of NCMs in the biology of eculizumab resistance in TA-TMA. Multiple available therapies aim to prevent cell senescence and are therefore of significant interest in TA-TMA.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.