Tocilizumab treatment leads to early resolution of lymphopenia and myeloid dysregulation in patients hospitalized with COVID-19

Abstract

Tocilizumab, an anti-interleukin-6 receptor inhibitor, is recommended in global treatment guidelines for patients hospitalized with severe COVID-19. Using proteomic and transcriptomic analysis, we characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial, to assess the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysfunction, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysfunction associated with severe COVID-19, thus defining an anti-inflammatory mechanism of action for the beneficial effects of tocilizumab in patients hospitalized with COVID-19.

Trajectories of host-response biomarkers and inflammatory subphenotypes in COVID-19 patients across the spectrum of respiratory support

“…Although our analyses cannot control for indication bias or differences in biology from SARS-CoV-2 variants, our results indicate that administered host-targeted therapies in COVID-19 impact prognostic biomarker levels in distinct ways. We found markedly higher IL-6 levels in patients treated with anti-IL6 therapies, consistent with the expected pharmacodynamic effects of tocilizumab and sarilumab binding both the membrane bound and soluble IL-6 receptor, as shown in the COVACTA trial[28]. Conversely, receipt of any immunomodulatory treatment was associated with markedly lower levels of Ang-2, perhaps indicating a protective effect of immunomodulation on endothelial function and vascular biology.…”

A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling

“…7D). We define a pan-myeloid ENRAGE program of coordinately-expressed genes in the airways and blood of COVID-19 patients that is prognostic for severe outcomes and is robust across 7 cohorts 2,[5][6][7]11,12,14,36,37 . EN-RAGE + cells express multiple phenotypic hallmarks of MDSCs by cell surface protein analysis: decreased capacity for antigen presentation and co-stimulation through HLA-DR and CD40, and increased potential to suppress T cells through PD-L1.…”

“…This study supports a working model whereby IL-6 differentiates myeloid cells from both monocytic and granulocytic lineages to a suppressive phenotype characterized by low antigen presentation on HLA-DR and increased expression of multiple factors that can suppress T cells (IL-10, PD-L1, TGF-β1) ( Figure 7D ). We define a pan-myeloid ENRAGE program of coordinately-expressed genes in the airways and blood of COVID-19 patients that is prognostic for severe outcomes and is robust across 7 cohorts(2, 5–7, 11, 12, 14, 36, 37). EN-RAGE + cells express multiple phenotypic hallmarks of MDSCs by cell surface protein analysis: decreased capacity for antigen presentation and co-stimulation through HLA-DR and CD40, and increased potential to suppress T cells through PD-L1.…”

“…Finally, to understand the role of IL-6 in patients, we examined the effect of tocilizumab treatment on the EN-RAGE myeloid state in COVID-19 patients and effect on T cells using longitudinal samples from the COVACTA study (14,34). Blockade of IL-6 signaling reduced expression of many genes in the EN-RAGE program and increased T cell signature expression after 3 or 7 days of tocilizumab treatment compared with placebo (Figure 6A, E; Benjamini-Hochberg FDR<0.05).…”

“…Altered myeloid cell expression states, including the accumulation of cells with hallmarks of myeloid-derived suppressor cells (MDSC), are consistent features in the blood of COVID-19 patients, and serve as a hallmark of severity [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] . Monocytes and granulocytes associated with increased COVID-19 severity exhibit low expression of HLA-DR, and high expression of hallmark MDSC genes such as S100A12 (EN-RAGE), and can impair T cell activation via contactdependent (i.e., PD-L1) and soluble mechanisms, including IL-10, TGF-β, arginase 1, IDOdependent tryptophan metabolism, and reactive oxygen and nitrogen species (reviewed in [19][20][21][22] ).…”