Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics.

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we sought to determine the molecular features of breast cancer-associated MDSCs using the widely studied mouse model based on the mouse mammary tumor virus (MMTV) promoter-driven expression of the polyomavirus middle T oncoprotein (MMTV-PyMT). To identify MDSCs in an unbiased manner, we used single-cell RNA sequencing to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice with wild-type controls. Our computational analysis of 14,646 single-cell transcriptomes revealed that MDSCs emerge through an aberrant neutrophil maturation trajectory in the spleen that confers them an immunosuppressive cell state. We establish the MDSC-specific gene signature and identify CD84 as a surface marker for improved detection and enrichment of MDSCs in breast cancers.

Elevated frequencies of CD14+HLA-DRlo/neg MDSCs in COVID-19 patients.

BACKGROUND: The immune responses, hyper-inflammation or immunosuppression, may be closely related to COVID-19 progression. We aimed to evaluate the changes of frequency of CD14+HLA-DRlo/neg MDSCs, a population of cells with potent immunosuppressive capacity, in COVID-19 patients. METHODS: The levels of CD14+HLA-DRlo/neg MDSCs were determined by flow cytometry in 27 COVID-19 patients, and their association with clinical characteristics and laboratory data were analyzed. RESULTS: The frequency of CD14+HLA-DRlo/neg MDSCs was elevated in COVID-19 patients, particularly severe patients. A follow-up comparison revealed a decline of CD14+HLA-DRlo/neg MDSCs percentages in most patients 1 day after testing negative for SARS-CoV-2 nucleic acid, but the levels of CD14+HLA-DRlo/neg MDSCs were still greater than 50.0% in 3 ICU patients 4-10 days after negative SARS-CoV-2 results. Elevated frequency of CD14+HLA-DRlo/neg MDSCs was positively correlated with oropharyngeal viral loads and length of hospital stay, while negatively correlated with lymphocyte counts and serum albumin. Moreover, strong correlations were observed between the frequency of CD14+HLA-DRlo/neg MDSCs and T cell subsets, NK cell counts, and B cell percentages. The frequency of CD14+HLA-DRlo/neg MDSCs could be used as a predictor of COVID-19 severity. CONCLUSIONS: A high frequency of CD14+HLA-DRlo/neg MDSCs, especially in severe patients, may indicate an immunoparalysis status and could be a predictor of disease severity and prognosis.

Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients.

Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed ~140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with ~30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-γ production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease.

Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity.

The immunopathology of coronavirus disease 2019 (COVID-19) remains enigmatic, causing immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSCs) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied the blood and airways of patients with COVID-19 across disease severities at multiple time points. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of patients with COVID-19 compared with healthy controls. M-MDSCs isolated from patients with COVID-19 suppressed T cell proliferation and IFN-γ production partly via an arginase 1-dependent (Arg-1-dependent) mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. Patients with COVID-19 had fewer T cells and downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expanded in the blood of patients with COVID-19, suppressed T cells, and were strongly associated with disease severity, indicating a role for M-MDSCs in the dysregulated COVID-19 immune response.