Grossmolloy0656

PURPOSE Using standard-of-care CT images obtained from patients with a diagnosis of non-small cell lung cancer (NSCLC), we defined radiomics signatures predicting the sensitivity of tumors to nivolumab, docetaxel, and gefitinib. SB590885 cost EXPERIMENTAL DESIGN Data were collected prospectively and analyzed retrospectively across multicenter clinical trials [nivolumab, n = 92, CheckMate017 (NCT01642004), CheckMate063 (NCT01721759); docetaxel, n = 50, CheckMate017; gefitinib, n = 46, (NCT00588445)]. Patients were randomized to training or validation cohorts using either a 41 ratio (nivolumab 72T20V) or a 21 ratio (docetaxel 32T18V; gefitinib 31T15V) to ensure an adequate sample size in the validation set. Radiomics signatures were derived from quantitative analysis of early tumor changes from baseline to first on-treatment assessment. For each patient, 1,160 radiomics features were extracted from the largest measurable lung lesion. Tumors were classified as treatment sensitive or insensitive; reference standard was median search.We reported that protein kinase C-η (PKCη) forms a novel (to our knowledge) signaling complex with the checkpoint inhibitory protein CTLA-4 in regulatory T cells (Tregs). This complex is required for the contact-dependent suppressive activity of Tregs, including suppression of antitumor immunity. However, the importance of PKCη in protective immunity mediated by T effector cells remains unclear. We used mice with germline or conditional Treg-specific deletion of Prkch, the PKCη-encoding gene, to explore CD8+ T cell-dependent antiviral immunity using the lymphocytic choriomeningitis virus Armstrong strain acute infection model as well as the in vitro activation of murine or human CD8+ T cells. Five days following infection, germline Prkch -/- mice displayed enhanced viral clearance compared with control mice. Similarly, Prkch Treg-specific conditional knockout mice also showed improved viral clearance and displayed enhanced expression of granzyme B and IFN-γ by both virus-specific and total CD8+ T cells, demonstrating that enhanced viral clearance in germline Prkch -/- mice is caused by PKCη deficiency in Tregs and the resulting functional defect of Prkch -/- Tregs. In addition, purified Prkch -/- mouse CD8+ T cells as well as PRKCH knockdown human CD8+ T cells displayed intact, or even enhanced, T cell activation in vitro as measured by proliferation and expression of granzyme B and IFN-γ. Thus, global PKCη deletion does not impair overall CD8+ T cell-mediated immunity, including antiviral immunity, implying that selective pharmacological PKCη inhibition could be safely used in vivo to inhibit undesired contact-dependent suppression by Tregs and, thus, enhance tumor-specific and, likely, virus-specific immunity. Copyright © 2020 by The American Association of Immunologists, Inc.The B cell adaptor protein (BCAP) is a multimodular regulator of inflammatory signaling in diverse immune system cells. BCAP couples TLR signaling to phosphoinositide metabolism and inhibits MyD88-directed signal transduction. BCAP is recruited to the TLR signalosome forming multitypic interactions with the MAL and MyD88 signaling adaptors. In this study, we show that indirect dimerization of BCAP TIR is required for negative regulation of TLR signaling. This regulation is mediated by a transcription factor Ig (TIG/IPT) domain, a fold found in the NF-κB family of transcription factors. We have solved the crystal structure of the BCAP TIG and find that it is most similar to that of early B cell factor 1 (EBF1). In both cases, the dimer is stabilized by a helix-loop-helix motif at the C terminus and interactions between the β-sheets of the Ig domains. BCAP is exclusively localized in the cytosol and is unable to bind DNA. Thus, the TIG domain is a promiscuous dimerization module that has been appropriated for a range of regulatory functions in gene expression and signal transduction. Copyright © 2020 The Authors.Negative regulation of innate immunity is essential to avoid autoinflammation. In Drosophila melanogaster, NF-κB signaling-mediated immune responses are negatively regulated at multiple levels. Using a Drosophila RNA interference in vitro screen, we identified a set of genes inhibiting immune activation. Four of these genes encode members of the chromatin remodeling Osa-containing Brahma (BAP) complex. Silencing additional two genes of the BAP complex was shown to have the same phenotype, confirming its role in immune regulation in vitro. In vivo, the knockdown of osa and brahma was shown to enhance the expression of the Toll pathway-mediated antimicrobial peptides when the flies were challenged with Gram-positive bacteria Micrococcus luteus In this setting, osa knockdown had a particularly strong effect on immune effectors that are predominantly activated by the Imd pathway. Accordingly, Drosophila NF-κB Relish expression was increased by osa silencing. These transcriptional changes were associated with enhanced survival from M. luteus + E. faecalis infection. Besides regulating the expression of immune effector genes, osa RNA interference decreased the expression of a large group of genes involved in metabolism, particularly proteolysis. Of note, the expression of the recently characterized, immune-inducible gene Induced by Infection (IBIN) was diminished in osa knockdown flies. Although IBIN has been shown to modulate metabolism upon infection, the expression of selected Osa-regulated metabolism genes was not rescued by overexpressing IBIN. We conclude that the BAP complex regulates expression of genes involved in metabolism at least partially independent or downstream of IBIN Moreover, Osa affects the NF-κB-mediated immune response by regulating Drosophila NF-κB factor Relish expression. Copyright © 2020 by The American Association of Immunologists, Inc.COPA syndrome is a recently described Mendelian autoimmune disorder caused by missense mutations in the coatomer protein complex subunit α (COPA) gene. Patients with COPA syndrome develop arthritis and lung disease that presents as pulmonary hemorrhage or interstitial lung disease (ILD). Immunosuppressive medications can stabilize the disease, but many patients develop progressive pulmonary fibrosis, which requires life-saving measures, such as lung transplantation. Because very little is understood about the pathogenesis of COPA syndrome, it has been difficult to devise effective treatments for patients. To date, it remains unknown which cell types are critical for mediating the disease as well as the mechanisms that lead to autoimmunity. To explore these issues, we generated a CopaE241K/+ germline knock-in mouse bearing one of the same Copa missense mutations in patients. Mutant mice spontaneously developed ILD that mirrors lung pathology in patients, as well as elevations of activated cytokine-secreting T cells.