Single-Cell Transcriptomics Reveals Pre-existing COVID-19 Vulnerability Factors in Lung Cancer Patients

UNLABELLED: Coronavirus disease 2019 (COVID-19) and cancer are major health threats, and individuals may develop both simultaneously. Recent studies have indicated that patients with cancer are particularly vulnerable to COVID-19, but the molecular mechanisms underlying the associations remain poorly understood. To address this knowledge gap, we collected single-cell RNA-sequencing data from COVID-19, lung adenocarcinoma, small cell lung carcinoma patients, and normal lungs to perform an integrated analysis. We characterized altered cell populations, gene expression, and dysregulated intercellular communication in diseases. Our analysis identified pathologic conditions shared by COVID-19 and lung cancer, including upregulated TMPRSS2 expression in epithelial cells, stronger inflammatory responses mediated by macrophages, increased T-cell response suppression, and elevated fibrosis risk by pathologic fibroblasts. These pre-existing conditions in patients with lung cancer may lead to more severe inflammation, fibrosis, and weakened adaptive immune response upon COVID-19 infection. Our findings revealed potential molecular mechanisms driving an increased COVID-19 risk in patients with lung cancer and suggested preventive and therapeutic targets for COVID-19 in this population. IMPLICATIONS: Our work reveals the potential molecular mechanisms contributing to the vulnerability to COVID-19 in patients with lung cancer

The Challenges and Opportunities of scRNA-Seq in COVID-19 Research and Clinical Translation

The application of single-cell RNA sequencing in COVID-19 research has greatly improved our understanding of COVID-19 pathogenesis and immunological characteristics. In this commentary, we discuss the current challenges, limitations, and perspectives in harnessing the power of single-cell RNA sequencing to accelerate both basic research and therapeutic development for COVID-19 and other emerging infectious diseases

Creep behaviors and microstructural stabilities of Co-Al-W-Ta-Ti-based Superalloys

In last decade, the discovery of high-temperature stable γ\u27-Co3(Al, W) phase in Co-Al-W-base alloys motivated plentiful interests in designing the next generation γ\u27-strengthened Co-based superalloys. Continued efforts have been focused on increasing the γ\u27 solvus temperature and enhancing the γ/γ\u27 microstructural stability as well as improving the creep resistance at elevated temperatures in this class of superalloys. In the present work, the effects of Ti and Ta additions on the creep properties and the microstructural stabilities of Co-Al-W-Ta-Ti-based superalloys are investigated by means of integrated the experimental and computational approaches. The chemistry design of Co-Al-W-Ta-Ti alloys was supported by the thermodynamic calculations of phase stability using the Co-base alloys database in PandatTMdeveloped by the CALPHAD method. The atomic and the electronic structures for solute-strengthened (001) anti-phase boundaries (APB) of Co3(Al, TM) are investigated by first-principles calculations based on the density functional theory (DFT), where TM denotes transition metals. It is observed that at 1000oC, the creep property of a Co-based single-crystal superalloy containing Ti and Ta is superior in comparison with the other reported Co-Al-W-base single crystal alloys and the 1st generation commercial Ni-base single-crystal superalloys. The different creep behaviors between Co-based and Ni-based superalloys indicate that the creep deformation mechanism of Co-based superalloys is mainly associated with the stacking faults and anti-phase boundaries. Moreover, Co-Al-W-Ta-Ti model alloys have been developed with the variation of alloying additions, recently. Our designed alloys show better microstructural stability at higher temperature as well as high γ\u27 solvus temperature. DFT-based first principles calculations further reveal the complex electron structures induced by the variation of the lattice distortion around the fault layers in the solute-containing (001) APB. It is observed that the formation of the (001) APB in Co3Al changes the Co-centered deformation electron density isosurface from the typical tetrahedral shape in the FCC lattice into the “S” shape. With the segregation of solute atoms at (001) APB, the bond strength around the fault layers are increased by the electron redistribution by forming chemical bonds with Co, providing fundamental insights on interactions among alloying elements and their effects on APB and creep properties. The current study is helpful for continuous efforts on alloy design and development to improve temperature capability of γ\u27-strengthened Co-base superalloys

Preventive Treatment with a CD73 Small Molecule Inhibitor Enhances Immune Surveillance in K-Ras Mutant Pancreatic Intraepithelial Neoplasia

Immunoprevention is an emerging consideration for solid tumors, including pancreatic ductal adenocarcinoma (PDAC). We and others have shown that Kras mutations in genetic models of spontaneous pancreatic intraepithelial neoplasia (PanIN), which is a precursor to PDAC, results in CD73 expression in the neoplastic epithelium and some populations of infiltrating immune cells, including macrophages and CD8 T cells. CD73 is an ecto-enzyme that converts extracellular adenosine monophosphate to adenosine, a critical immune inhibitory molecule in PDAC. We hypothesized inhibition of CD73 would reduce the incidence of PanIN formation and alter the immune microenvironment. To test our hypothesis, we used the KrasG12D; PdxCre1 (KC) genetically engineered mouse model and tested the utility of AB-680, a small molecule inhibitor targeting CD73, to inhibit PanIN progression. AB-680, or vehicle control, was administered using oral gavage delivery 3 days/week at 10 mg/kg, beginning when the mice were 2 months old and lasting 3 months. We euthanized the mice at 5 months old. In the KC model, we quantified significantly less pancreatitis, early and advanced PanIN, and quantified a significant increase in M1 macrophages in AB-680-treated mice. Single-cell RNA sequencing (scRNA-seq) of pancreata of AB-680-treated mice revealed increased infiltration of CD4+ T cells, CD8+ T cells, and mature B cells. The scRNA-seq analysis showed that CD73 inhibition reduced M2 macrophages, acinar, and PanIN cell populations. CD73 inhibition enhanced immune surveillance and expanded unique clonotypes of TCR and BCR, indicating that inhibition of CD73 augments adaptive immunity early in the neoplastic microenvironment. Prevention Relevance: Previous studies found PanIN lesions in healthy pancreata. Not all progress to PDAC, suggesting a window for enhanced antitumor immunity through immunoprevention therapy. CD73 inhibition in our study prevents PanIN progression, reduces immune-suppressive macrophages and expands TCR and BCR unique clonotypes, highlighting an encouraging therapeutic avenue for high-risk individuals

Supplementary Figure 1 from Single-Cell Transcriptomics Reveals Pre-existing COVID-19 Vulnerability Factors in Lung Cancer Patients

Supplementary Figure 1. An overview of four-level hierarchical annotation of single cells in lung tissue.</p

Supplementary Table 1 from Single-Cell Transcriptomics Reveals Pre-existing COVID-19 Vulnerability Factors in Lung Cancer Patients

Supplementary Table 1. The clinical characteristics of included human subjects.</p

Supplementary Figure 2 from Single-Cell Transcriptomics Reveals Pre-existing COVID-19 Vulnerability Factors in Lung Cancer Patients

Supplementary Figure 2. ACE2 expression in alveolar and airway epithelial cells from COVID-19 and lung cancers.</p

Supplementary Figure 6 from Single-Cell Transcriptomics Reveals Pre-existing COVID-19 Vulnerability Factors in Lung Cancer Patients

Supplementary Figure 6. The contribution of cell populations to signaling pathways.</p

Supplementary Figure 3 from Single-Cell Transcriptomics Reveals Pre-existing COVID-19 Vulnerability Factors in Lung Cancer Patients

Supplementary Figure 3. Macrophage subpopulations and functional characterization.</p