Frontiers in immunology
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Frontiers in immunology · Jan 2020
Observational StudyDynamics of Serum Tumor Markers Can Serve as a Prognostic Biomarker for Chinese Advanced Non-small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors.
Background: Serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cytokeratin 19 fragment (CYFRA21-1) and squamous-cell carcinoma-related antigen (SCC-Ag) are routinely used for monitoring the response to chemotherapy or targeted therapy in advanced-stage non-small cell lung cancer (NSCLC), however their role in immunotherapy remains unclear. The aim of this study was to investigate whether dynamics of these serum markers were associated with the efficacy and prognosis of Chinese late-stage NSCLC patients treated with programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors. Methods: We initiated a longitudinal prospective study on advanced NSCLC patients treated with PD-1/PD-L1 inhibitors in Chinese PLA general hospital (Beijing, China). ⋯ So as in patients with squamous cell carcinoma, meaningful improvements in at least 2 out of 4 biomarkers were linked to better ORR (0.42 vs. 0.08, p = 0.014), longer PFS (median: 13.1 vs. 5.6 months, p = 0.001), and OS (median: 25.6 vs. 10.9 months, p = 0.06). Conclusions: The dynamic change of CEA, CA125, CYFRA21-1, and SCC-Ag from baseline have prognostic value for late-stage NSCLC patients treated with PD-1/PD-L1 inhibitors. Decrease of associated biomarkers serum levels were associated with favorable clinical outcomes.
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The inability of patients with CVID to mount specific antibody responses to pathogens has raised concerns on the risk and severity of SARS-CoV-2 infection, but there might be a role for protective T cells in these patients. SARS-CoV-2 reactive T cells have been reported for SARS-CoV-2 unexposed healthy individuals. Until now, there is no data on T cell immunity to SARS-CoV-2 infection in CVID. ⋯ Taken together, SARS-CoV-2 reactive T cells are detectable in unexposed CVID patients albeit with lower recognition frequencies and polyfunctional potential. Frequencies of triple-functional reactive CD4+ cells might provide a marker to distinguish HCoV cross-reactive from SARS-CoV-2 specific T cell responses. Our data provides evidence, that anti-viral T cell immunity is not relevantly impaired in most CVID patients.
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Frontiers in immunology · Jan 2020
Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer.
Colorectal cancer (CRC) patients, especially those with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors, whose sensitivity to immune checkpoint inhibitors (ICIs) is significantly higher than that of patients with microsatellite-stable (MSS)/microsatellite instability-low (MSI-L) tumors, have derived clinical benefits from immunotherapy. Most studies have not systematically evaluated the immune characteristics and immune microenvironments of MSI-H and MSS/MSI-L CRCs. We analyzed the relationship between the MSI status and prognosis of ICI treatment in an immunotherapy cohort. ⋯ In addition, subtype analysis showed that COAD and READ might have different immune microenvironments. MSI-H CRC may have an inflammatory tumor microenvironment and increased sensitivity to ICIs. Unlike those of MSI-H READ, the immune characteristics of MSI-H COAD may be consistent with those of MSI-H CRC.
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Frontiers in immunology · Jan 2020
"Small" Intestinal Immunopathology Plays a "Big" Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor.
Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. ⋯ Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS.