Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy with a complex tumor ecosystem. How the interplay between tumor cells, EBV, and the microenvironment contributes to NPC progression and immune evasion remains unclear. Here we performed single-cell RNA sequencing on ~104,000 cells from 19 EBV + NPCs and 7 nonmalignant nasopharyngeal biopsies, simultaneously profiling the transcriptomes of malignant cells, EBV, stromal and immune cells. Overall, we identified global upregulation of interferon responses in the multicellular ecosystem of NPC. Notably, an epithelial-immune dual feature of malignant cells was discovered and associated with poor prognosis. Functional experiments revealed that tumor cells with this dual feature exhibited a higher capacity for tumorigenesis. Further characterization of the cellular components of the tumor microenvironment (TME) and their interactions with tumor cells revealed that the dual feature of tumor cells was positively correlated with the expression of co-inhibitory receptors on CD8 + tumor-infiltrating T cells. In addition, tumor cells with the dual feature were found to repress IFN-γ production by T cells, demonstrating their capacity for immune suppression. Our results provide new insights into the multicellular ecosystem of NPC and offer important clinical implications.
BackgroundInterleukin-9 (IL-9) was reported as an active participant in the pathogenesis of allergic asthma. This study aimed to investigate the major source ofIL-9 and its effect on interferon γ (IFN-γ) and immunoglobulin (Ig) secretion by B cells.MethodsWe isolated peripheral blood mononuclear cells from children with allergic asthma and healthy children. IL-9, IL-4 and IFN-γ expression were detected by ELISA, ELISpot and Flowcytometry. Expression of transcription factor PU.1 was measured by Western Blot. We evaluated the effect of IL-9 on B cell activation and Ig production.ResultsResults showed that compared with healthy children, levels of IL-9, IL-4 and PU.1 were elevated and levels of IFN-γ were lower in children with allergic asthma. IL-9-expressing CD4+ T cells did not co-express IL-4. Exogenous IL-9 inhibited IFN-γ production in a dose-dependent manner. Antigen-specific Th9 cells existed in children with house dust mite allergic asthma. IL-9 up-regulated expression of CD69 and CD25 on B cells and combination of IL-9 and IL-4 enhanced IgE production.ConclusionsIn conclusion, our results showed that Th9 cells may be the major source of IL-9 in children with allergic asthma. In these patients, IL-9 impairs IFN-γ production and synergistically promotes IL-4-induced IgE secretion.
BackgroundA major current challenge is to exploit tertiary lymphoid structures (TLSs) to promote the lymphocyte infiltration, activation and differentiation by tumor antigens to increase antitumor immune responses. The mechanisms that underlie the role of TLS formation in the adaptive immune responses against nasopharyngeal carcinoma (NPC) remain largely unknown.MethodsCell populations and the corresponding markers were identified by single-cell RNA sequencing and fluorescence-activated cell sorting analysis. In vitro differentiation experiments were used to simulate the generation, regulation and function of the Th-CXCL13 cell subset in the tumor microenvironment of NPC. These were followed by histological evaluation of the colocalization of tumor-associated B cells (TABs) and Th-CXCL13 cells within TLSs, and statistical analysis of the relationship between the cells in TLSs and overall survival.ResultsA PD-1+CXCR5−CD4+ Th-CXCL13 cell subset was identified in NPC. This subset was a major source of CXCL13, representing the majority of the CD4+ T cells at levels comparable with Th1 and Tfh cells present in the TLSs. Monocytes activated by toll-like receptor 4 agonists served as the antigen-presenting cells that most efficiently triggered the expansion of Th-CXCL13 cells. Transforming growth factor beta 1 (TGF-β1) stimulation and activation of Sox4 were critical for the induction and polarization of Th-CXCL13 cells in this process. The potential functional contributions of TABs recruited by Th-CXCL13 cells which induced plasma cell differentiation and immunoglobulin production via interleukin-21 and CD84 interactions in the TLSs demonstrated improved survival.ConclusionsInduction of Th-CXCL13 cells links innate inflammation to immune privilege in tumor-associated TLSs and might predict better survival.
Background. Recently, a large-scale novel coronavirus pneumonia (NCP) outbreak swept China. As of Feb. 9, 2020, a total of 40,260 patients have been diagnosed with NCP, and 23,589 patients were suspected to have infected by the 2019 novel coronavirus (COVID-19), which puts forward a great challenge for public health and clinical treatment in China. Until now, we are in the high-incidence season of NCP. Thus, the analysis of the transmissibility change of NCP and its potential factors may provide a reliable reference for establishing effective prevention and control strategies. Method. By means of the method of calculating the instantaneous basic reproduction number R0t proposed by Cori et al. (2013), we use R0t to describe the transmissibility change of COVID-19 in China, 2019-2020. In addition, the Baidu Index (BDI) and Baidu Migration Scale (BMS) were selected to measure the public awareness and the effect of Wuhan lockdown (restricted persons in Wuhan outflow from the epidemic area) strategy, respectively. The Granger causality test (GCT) was carried out to explore the association between public awareness, the effect of the Wuhan lockdown strategy, and the transmissibility of COVID-19. Results. The estimated averaged basic reproduction number of NCP in China was 3.44 with 95% CI (2.87, 4.0) during Dec. 8, 2019, to Feb. 9, 2020. The instantaneous basic reproduction numbers (R0t) have two waves and reaching peaks on Jan. 8 and Jan. 27, respectively. After reaching a peak on Jan. 27, R0t showed a continuous decline trend. On Feb. 9, R0t has fallen to 1.68 (95% CI: 1.66, 1.7), but it is still larger than 1. We find a significantly negative association between public awareness and the transmissibility change of COVID-19, with one unit increase in cumulative BDI leading to a decrease of 0.0295% (95% CI: 0.0077, 0.051) R0t. We also find a significantly negative association between the effect of the Wuhan lockdown strategy and the transmissibility change of COVID-19, and a one unit decrease in BMS may lead to a drop of 2.7% (95% CI: 0.382, 4.97) R0t. Conclusion. The current prevention and control measures have effectively reduced the transmissibility of COVID-19; however, R0t is still larger than the threshold 1. The results show that the government adopting the Wuhan lockdown strategy plays an important role in restricting the potential infected persons in Wuhan outflow from the epidemic area and avoiding a nationwide spread by quickly controlling the potential infection in Wuhan. Meanwhile, since Jan. 18, 2020, the people successively accessed COVID-19-related information via the Internet, which may help to effectively implement the government’s prevention and control strategy and contribute to reducing the transmissibility of NCP. Therefore, ongoing travel restriction and public health awareness remain essential to provide a foundation for controlling the outbreak of COVID-19.
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