ABSTRACT
Systemic immunosuppression greatly affects the chemotherapeutic antitumor effect. Here, we showed that CD19+ extracellular vesicles (EVs) from B cells through CD39 and CD73 vesicle-incorporated proteins hydrolyzed ATP from chemotherapy-treated tumor cells into adenosine, thus impairing CD8+ T cell responses. Serum CD19+ EVs were increased in tumor-bearing mice and patients. Patients with fewer serum CD19+ EVs had a better prognosis after chemotherapy. Upregulated hypoxia-inducible factor-1α (HIF-1α) promoted B cells to release CD19+ EVs by inducing Rab27a mRNA transcription. Rab27a or HIF-1α deficiency in B cells inhibited CD19+ EV production and improved the chemotherapeutic antitumor effect. Silencing of Rab27a in B cells by inactivated Epstein-Barr viruses carrying Rab27a siRNA greatly improved chemotherapeutic efficacy in humanized immunocompromised NOD PrkdcscidIl2rg-/- mice. Thus, decreasing CD19+ EVs holds high potential to improve the chemotherapeutic antitumor effect.
Subject(s)
B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Extracellular Vesicles/immunology , Animals , Antigens, CD19/immunology , Cell Line , Cell Line, Tumor , Female , HEK293 Cells , Herpesvirus 4, Human/immunology , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/immunology , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , NIH 3T3 Cells , RNA, Messenger/immunology , Transcription, Genetic/immunology , rab27 GTP-Binding Proteins/immunologyABSTRACT
Long-term exposure to low polycyclic aromatic hydrocarbon (PAH) concentration may ave detrimental effects, including changing platelet indices. Effects of chronic exposure to low PAH concentrations have been evaluated in cross-sectional, but not in longitudinal studies, to date. We aimed to assess the effects of long-term exposure to the low-concentration PAHs on alterations in platelet indices in the Chinese population. During 2014-2017, we enrolled 222 participants who had lived in a village in northern China, 1-2 km downwind from a coal plant, for more than 25 years, but who were not employed by the plant or related businesses. During three follow-ups, annually in June, demographic information and urine and blood samples were collected. Eight PAHs were tested: namely 2-hydroxynaphthalene, 1-hydroxynaphthalene, 2-hydroxyfluorene, 9-hydroxyfluorene (9-OHFlu), 2-hydroxyphenanthrene (2-OHPh), 1-hydroxyphenanthrene (1-OHPh), 1-hydroxypyrene (1-OHP), and 3-hydroxybenzo [a] pyrene. Five platelet indices were measured: platelet count (PLT), platelet distribution width (PDW), mean platelet volume (MPV), platelet crit, and the platelet-large cell ratio. Generalized mixed and generalized linear mixed models were used to estimate correlations between eight urinary PAH metabolites and platelet indices. Model 1 assessed whether these correlations varied over time. Models 2 and 3 adjusted for additional personal information and personal habits. We found the following significant correlations: 2-OHPh (Model1 ß1 = 18.06, Model2 ß2 = 18.54, Model ß3 = 18.54), 1-OHPh (ß1 = 16.43, ß2 = 17.42, ß3 = 17.42), 1-OHP(ß1 = 13.93, ß2 = 14.03, ß3 = 14.03) with PLT, as well as 9-OHFlu with PDW and MPV (odds ratio or Model3 ORPDW[95%CI] = 1.64[1.3-2.06], ORMPV[95%CI] = 1.33[1.19-1.48]). Long-term exposure to low concentrations of PAHs, indicated by2-OHPh, 1-OHPh, 1-OHP, and 9-OHFlu, as urinary biomarkers, affects PLT, PDW, and MPV. 9-OHFlu increased both PDW and MPV after elimination of the effects of other PAH exposure modes.
Subject(s)
Polycyclic Aromatic Hydrocarbons , Humans , Polycyclic Aromatic Hydrocarbons/metabolism , Longitudinal Studies , Cross-Sectional Studies , Biomarkers/urine , Mean Platelet VolumeABSTRACT
DNA vaccine is one of the most attractive project in the research of vaccine now. DNA tumor vaccines mainly include tumor-associated-antigens-based completed, epitope, idiotope determinants DNA vaccine, fusion DNA vaccines, RNA self-replicating vaccines, dendritic cell-based tumor vaccines etc. The recent developments are discussed in the article.