Browsing by Author "Carr, Steven A."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Cell-surface Milieu Remodeling in Human Dendritic Cell Activation
    (The American Association of Immunologists, 2024) Udeshi, Namrata D.; Xu, Charles; Jiang, Zuzhi; Gao, Shihong Max; Yin, Qian; Luo, Wei; Carr, Steven A.; Davis, Mark M.; Li, Jiefu; Microbiology and Immunology, School of Medicine
    Dendritic cells (DCs) are specialized sentinel and APCs coordinating innate and adaptive immunity. Through proteins on their cell surface, DCs sense changes in the environment, internalize pathogens, present processed Ags, and communicate with other immune cells. By combining chemical labeling and quantitative mass spectrometry, we systematically profiled and compared the cell-surface proteomes of human primary conventional DCs (cDCs) in their resting and activated states. TLR activation by a lipopeptide globally reshaped the cell-surface proteome of cDCs, with >100 proteins upregulated or downregulated. By simultaneously elevating positive regulators and reducing inhibitory signals across multiple protein families, the remodeling creates a cell-surface milieu promoting immune responses. Still, cDCs maintain the stimulatory-to-inhibitory balance by leveraging a distinct set of inhibitory molecules. This analysis thus uncovers the molecular complexity and plasticity of the cDC cell surface and provides a roadmap for understanding cDC activation and signaling.
  • Thumbnail Image
    Item
    Genomic Profiling of Lung Adenocarcinoma in Never-Smokers
    (American Society of Clinical Oncology, 2021) Devarakonda, Siddhartha; Li, Yize; Martins Rodrigues, Fernanda; Sankararaman, Sumithra; Kadara, Humam; Goparaju, Chandra; Lanc, Irena; Pepin, Kymberlie; Waqar, Saiama N.; Morgensztern, Daniel; Ward, Jeffrey; Masood, Ashiq; Fulton, Robert; Fulton, Lucinda; Gillette, Michael A.; Satpathy, Shankha; Carr, Steven A.; Wistuba, Ignacio; Pass, Harvey; Wilson, Richard K.; Ding, Li; Govindan, Ramaswamy; Medicine, School of Medicine
    Purpose: Approximately 10%-40% of patients with lung cancer report no history of tobacco smoking (never-smokers). We analyzed whole-exome and RNA-sequencing data of 160 tumor and normal lung adenocarcinoma (LUAD) samples from never-smokers to identify clinically actionable alterations and gain insight into the environmental and hereditary risk factors for LUAD among never-smokers. Methods: We performed whole-exome and RNA-sequencing of 88 and 69 never-smoker LUADs. We analyzed these data in conjunction with data from 76 never-smoker and 299 smoker LUAD samples sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. Results: We observed a high prevalence of clinically actionable driver alterations in never-smoker LUADs compared with smoker LUADs (78%-92% v 49.5%; P < .0001). Although a subset of never-smoker samples demonstrated germline alterations in DNA repair genes, the frequency of samples showing germline variants in cancer predisposing genes was comparable between smokers and never-smokers (6.4% v 6.9%; P = .82). A subset of never-smoker samples (5.9%) showed mutation signatures that were suggestive of passive exposure to cigarette smoke. Finally, analysis of RNA-sequencing data showed distinct immune transcriptional subtypes of never-smoker LUADs that varied in their expression of clinically relevant immune checkpoint molecules and immune cell composition. Conclusion: In this comprehensive genomic and transcriptome analysis of never-smoker LUADs, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker LUADs. Our findings also show that clinically actionable driver alterations are highly prevalent in never-smoker LUADs, highlighting the need for obtaining biopsies with adequate cellularity for clinical genomic testing in these patients.