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The SARS-CoV-2 infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Reports further indicate that COVID-19 patients may develop a wide spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS-CoV-2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID-19 patients, in a cohort of 248 individuals, of which171 were COVID-19 patients (74 with mild, 65 moderate, and 32 with severe disease) and 77were healthy controls. Dysregulated autoantibody serum levels, characterized mainly by elevated concentrations, occurred mostly in patients with moderate or severe COVID-19 infection, and was accompanied by a progressive disruption of physiologic IgG and IgA autoantibody signatures. A similar perturbation was found in patients with anosmia. Notably, autoantibody levels often accompanied anti-SARS-CoV-2 antibody concentrations, being both indicated by random forest classification as strong predictors of COVID-19 outcome, together with age. Moreover, higher levels of autoantibodies (mainly IgGs) were seen in the elderly with severe disease compared with young COVID-19 patients with severe disease. These findings suggest that the SARS-CoV-2 infection induces a broader loss of self-tolerance than previously thought, providing new ideas for therapeutic interventions.

The coronavirus disease 2019 (COVID-19) can evolve to clinical manifestations resembling systemic autoimmune diseases, with the presence of autoantibodies that are still poorly characterized. To address this issue, we performed a cross-sectional study of 246 individuals to determine whether autoantibodies targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS)-related molecules were associated with COVID-19-related clinical outcomes. Moderate and severe patients exhibited the highest autoantibody levels, relative to both healthy controls and patients with mild COVID-19 symptoms. Random Forest, a machine learning model, ranked anti-GPCR autoantibodies targeting downstream molecules in the RAS signaling pathway such as the angiotensin II type 1 and Mas receptor, and the chemokine receptor CXCR3 as the three strongest predictors of severe disease. Moreover, while the autoantibody network signatures were relatively conserved in patients with mild COVID-19 compared to healthy controls, they were disrupted in moderate and most perturbed in severe patients. Our data indicate that the relationship between autoantibodies targeting GPCRs and RAS-related molecules associates with the clinical severity of COVID-19, suggesting novel molecular pathways for therapeutic interventions.

COVID-19 shares the feature of autoantibody production with systemic autoimmune diseases. In order to understand the role of these immune globulins in the pathogenesis of the disease, it is important to explore the autoantibody spectra. Here we show, by a cross-sectional study of 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate with the clinical severity of COVID-19. Patients with moderate and severe disease are characterized by higher autoantibody levels than healthy controls and those with mild COVID-19 disease. Among the anti-GPCR autoantibodies, machine learning classification identifies the chemokine receptor CXCR3 and the RAS-related molecule AGTR1 as targets for antibodies with the strongest association to disease severity. Besides antibody levels, autoantibody network signatures are also changing in patients with intermediate or high disease severity. Although our current and previous studies identify anti-GPCR antibodies as natural components of human biology, their production is deregulated in COVID-19 and their level and pattern alterations might predict COVID-19 disease severity.

TNBC, or triple-negative breast cancer, is an aggressive type of breast cancer that is associated with a worse prognosis, higher rates of metastases, and a poorer outcome. Historically, TNBC has been proven challenging to treat, due to disease heterogeneity and the fact that the breast cancer tests negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) protein, and thus does not respond to traditional therapies. As such, treatment options for TNBC patients are extremely limited and there is a tremendous need to identify molecular targets and biomarkers that can offer novel targeted approaches. Additionally, due to disease heterogeneity in TNBC, it is important to subclassify TNBC based on prognostic markers and create tailored targeted therapies. ERRα, an orphan nuclear receptor, is an example of a prognostic marker that is correlated with a more aggressive disease progression and a worse outcome. However, ERRα is also a predictive marker for patient response to tamoxifen treatment of ER-negative and TNBC patients, indicating that there may be an alternative use for the selective estrogen modulator (SERM) tamoxifen in the context of TNBC. This led us to investigate whether there is a common pathway that is regulated by both ERRα and tamoxifen that would explain tamoxifen response in the context of TNBC cells. We performed a phosphoproteomic analysis of MDA-MB-231 cells, treated with either tamoxifen or XCT-790, an inverse agonist of ERRα, to identify common downstream targets of both ERRα and tamoxifen. Our findings indicate that the Ras-Raf-MEK-ERK signaling pathway is a common target of both XCT-790 and tamoxifen. This provides a novel treatment strategy that should be investigated for the treatment of TNBC patients, opens the door for investigation of novel targeted therapies, and highlights the need for the use of prognostic markers to identify sub-populations that benefit from individualized treatment strategies. Citation Format: David Musheyev, Adi Ronen, Miriam T. Lattin, Anya Alayev. Ras-Raf-MEK-ERK signaling pathway: a novel target of ERRα and tamoxifen in TNBC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1976.