Lung cancer is the leading cause of mortality worldwide. However, there is a lack of effective therapeutic strategies. Currently, tumor immunotherapy based on exosomes, which are secreted by a variety of cell types including tumor cells, has drawn particular attention and are suggested to have the potential for exploitation in tumor therapy. Nevertheless, the therapeutic efficacy mediated via tumor cell-derived exosomes is not satisfactory. Rab27a, one of the Rab family of small GTPases, has been suggested to be important in exosome secretion. Thus, the purpose of the present study was to examine whether exosomes derived from Rab27a‑overexpressing cells elicited more potent antitumor immunity. A Rab27a‑overexpressing line was established via transfection of a Rab27a overexpression vector into the human non-small-cell lung cancer cell line, A549. Exosomes were isolated and the typical exosomal protein markers, CD9, CD63, heat shock protein (Hsp) 70 and Hsp90, were found to be enriched in the exosomes derived from Rab27a‑overexpressing cells. Subsequently, these exosomes were demonstrated to be capable of upregulating major histocompatibility complex class II molecules as well as the co-stimulatory molecules CD80 and CD86 on dendritic cells (DCs), suggesting that more potent maturation of DCs was induced. Furthermore, DCs loaded with exosomes derived from Rab27-overexpressing cells significantly promoted CD4+ T cell proliferation in vitro. In addition, in vivo immunization of exosomes derived from Rab27a‑overexpressing cells inhibited tumor growth in a mouse model. It was also demonstrated that splenocytes from mice immunized with exosomes derived from Rab27-overexpressing cells expressed high levels of type I cytokines, including IL-2 and IFN-γ, which are important in the regulation of cell-mediated antitumor immunity. Collectively, it was demonstrated that exosomes derived from Rab27a‑overexpressing cancer cells elicited more potent antitumor immune effects, which may provide novel insights for the development of efficient exosome-based cancer vaccines.

BackgroundHistone deacetylase (HDAC) inhibitors, developed as promising anti-tumor drugs, exhibit their anti-inflammatory properties due to their effects on reduction of inflammatory cytokines.ObjectiveTo investigate the protective effect of butyrate, a HDAC inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice.MethodsALI was induced in Balb/c mice by intratracheally instillation of LPS (1 mg/kg). Before 1 hour of LPS administration, the mice received butyrate (10 mg/kg) orally. The animals in each group were sacrificed at different time point after LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of interleukin (IL)-1β and tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid (BALF) and concentrations of nitric oxide (NO) and myeloperoxidase (MPO) activity in lung tissue homogenates were measured by enzyme-linked immunosorbent assay (ELISA). Expression of nuclear factor (NF)-κB p65 in cytoplasm and nucleus was determined by Western blot analysis respectively.ResultsPretreatment with butyrate led to significant attenuation of LPS induced evident lung histopathological changes, alveolar hemorrhage, and neutrophils infiltration with evidence of reduced MPO activity. The lung wet/dry weight ratios, as an index of lung edema, were reduced by butyrate administration. Butyrate also repressed the production of TNF-α, IL-1β and NO. Furthermore, the expression of NF-κB p65 in nucleus was markedly suppressed by butyrate pretreatment.ConclusionsButyrate had a protective effect on LPS-induced ALI, which may be related to its effect on suppression of inflammatory cytokines production and NF-κB activation.

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Myasthenia gravis is a typical acetylcholine receptor (AChR) antibody-mediated autoimmune disease in which thymus frequently presents follicular hyperplasia or thymoma. It is now widely accepted that the thymus is probably the site of AChR autosensitization and autoantibody production. However, the exact mechanism that triggers intrathymic AChR antibody production is still unknown. T follicular helper cells, recently identified responsible for B cell maturation and antibody production in the secondary lymphoid organs, were involved in many autoimmune diseases. Newly studies found T follicular helper (Tfh) cells increased in the peripheral blood of myasthenia gravis (MG). Whether it appears in the thymus of MG and its role in the intrathymic B cells help and autoantibody production is unclear. Therefore, this study aims to determine in more detail whether Tfh/B cell interaction exist in MG thymus and to address its role in the ectopic germinal centers (GCs) formation and AChR antibody production. We observed the frequency of Tfh cells and its associated transcription factor Bcl-6, key cytokine IL-21 enhanced both in the thymocytes and peripheral blood mononuclear cells (PBMCs) of MG patients. In parallel, we also showed increased B cells and autoantibody titers in MG peripheral blood and thymus. Confocal microscope results demonstrated Tfh and B cells co-localized within the ectopic GCs in MG thymus, suggesting putative existence of Tfh/B cells interaction. In vitro studies further showed dynamic behavior of Tfh/B cells interaction and Tfh cells induced autoantibody secretion might through its effector cytokine IL-21. Altogether, our data demonstrated that intrathymic Tfh/B cells interaction played a key role in thymic ectopic GCs formation and anti-AChR antibody production, which might trigger MG occurrence.

ImportanceThe benefit of neoadjuvant camrelizumab plus chemotherapy for resectable stage IIIA or IIIB non–small cell lung cancer (NSCLC) remains unknown.ObjectiveTo assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy vs chemotherapy alone for patients with resectable stage IIIA or IIIB NSCLC.Design, Setting, and ParticipantsIn this randomized phase 2 clinical trial conducted at 2 hospitals in China, patients aged 18 to 70 years with resectable stage IIIA or IIIB (T3N2) NSCLC were enrolled between April 7, 2020, and January 12, 2022.InterventionsPatients were randomly assigned to receive 3 cycles of camrelizumab (200 mg) plus chemotherapy (nab-paclitaxel, 130 mg/m2, and platinum [cisplatin, 75 mg/m2; carboplatin, area under the curve, 5; or nedaplatin, 100 mg/m2]) or chemotherapy alone, followed by surgery after 4 to 6 weeks.Main Outcomes and MeasuresThe primary end point was the pathologic complete response (pCR) rate. Secondary end points included the major pathologic response (MPR) rate, objective response rate (ORR), event-free survival (EFS), and safety. Disease-free survival (DFS, defined as the time from surgery to disease recurrence or death from any cause) was analyzed post hoc. Efficacy was assessed on a modified intention-to-treat basis.ResultsNinety-four Chinese patients were randomized, and 88 (93.6%; median age, 61 years [IQR, 54-65 years]; 74 men [84.1%]) received allocated neoadjuvant treatment (43 received camrelizumab plus chemotherapy, and 45 received chemotherapy alone). Among these 88 patients, the pCR rate was 32.6% (14 of 43; 95% CI, 19.1%-48.5%) with camrelizumab plus chemotherapy vs 8.9% (4 of 45; 95% CI, 2.5%-21.2%) with chemotherapy alone (odds ratio, 4.95; 95% CI, 1.35-22.37; P = .008). The MPR rates were 65.1% (95% CI, 49.1%-79.0%) with camrelizumab plus chemotherapy and 15.6% (95% CI, 6.5%-29.5%) with chemotherapy alone. The radiographic ORRs were 72.1% (95% CI, 56.3%-84.7%) with camrelizumab plus chemotherapy and 53.3% (95% CI, 37.9%-68.3%) with chemotherapy alone. With a median follow-up of 14.1 months (IQR, 9.2-20.9 months), the median EFS and DFS were not reached in either group. The most common neoadjuvant treatment-related adverse events of grade 3 or higher were decreased white blood cell count (6 of 43 [14.0%] in the camrelizumab plus chemotherapy group vs 2 of 45 [4.4%] in the chemotherapy group) and decreased neutrophil count (3 of 43 [7.0%] in the camrelizumab plus chemotherapy group vs 5 of 45 [11.1%] in the chemotherapy group). No treatment-related deaths were reported.Conclusions and RelevanceThis randomized clinical trial found that among patients with resectable stage IIIA or IIIB (T3N2) NSCLC, camrelizumab plus chemotherapy, compared with chemotherapy alone, significantly improved the pCR rate with manageable toxic effects.Trial RegistrationClinicalTrials.gov Identifier: NCT04338620