We previously reported that antitumor B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. In this study, we defined additional mechanisms involved in B cell antitumor immunity. Administration of IL-2 significantly augmented the therapeutic efficacy of adoptively transferred tumor-draining lymph node (TDLN) B cells which express IL- 2R. Culture supernatant of purified B splenocytes harvested from the mice that received adoptive transfer of 4T1 TDLN B cells plus IL-2 administration produced larger amounts of IgG which bound to 4T1, resulting in 4T1 lysis. Furthermore, we detected CXCR4 expression on 4T1 TDLN B cells, and 4T1 tumor cells produced its ligand CXCL12. Transwell experiments demonstrated the chemoattraction of CXCR4-expressing 4T1 TDLN B cells towards CXCL12- producing 4T1 cells. Blockade of CXCR4 using a CXCR4-specific inhibitor, AMD3100, significantly reduced the killing of 4T1 tumor cells by 4T1 TDLN B cells. Blockade of FasL and CXCR4 concurrently inhibited B cell-mediated direct killing of tumor cells in an additive manner, indicating that both Fas/FasL and CXCL12/CXCR4 pathways are involved in the direct killing of 4T1 cells by 4T1 TDLN B cells. TDLN B cells produced perforin. Additional transwell experiments showed that effector B cells could directly kill tumor cells in cell-cell contact via the Fas/FasL and CXCR4/CXCL12 pathways as well as perforin, while without cell contact, perforin secreted by B cells led to tumor cell cytotoxicity. These findings underscore the diversity of function by which B cells can play an important role in the host immune response to tumor.
Mucin1 (MUC1) proteins represent a family of high molecular weight trans-membrane glycoproteins that protect epithelial cells and mediate signal transduction by communication with extracellular stimuli. On the other hand, MUC1 has been observed to be overexpressed and glycosylated in adenocarcinoma, making it an ideal molecular target for cancer treatment. MUC1 based antibody and specific chimeric antigen receptors (CARs) modified T/NK cells exhibit strong antibody-dependent or direct-cell cytotoxicity to MUC1 positive tumor cells. However, treatment failure with MUC1-targeted therapy was usually caused by tumor microenvironment (TME)-driven immune suppression. PD-L1 has been identified as a negative checkpoint molecule that promotes immune evasion of tumor cells. The interaction of PD-1 and PD-L1 inhibits the function of tumor-infiltrating lymphocytes (TILs) or infused T/NK cells while activating the negative immune-regulatory cells in TME, such as regulatory T-cells and MDSCs. To overcome these barriers, we engineered clinically applicable NK-92 cells by lentiviral gene transfer to express chimeric antigen receptors comprising an anti-MUC1 scFv antibody fusion protein with CD28-CD137 as a signaling moiety and truncated PD-1 peptide. NK92 cells expressing anti-MUC1 CAR specifically and efficiently lysed MUC1 positive tumor cells in vitro and in vivo. The safety of NK-92 cell administration has been demonstrated by numerous phase I clinical trials. In our study, 13 patients with different kinds of tumors (lung cancer, pancreatic cancer, colon cancer and ovarian cancer) with positive PD-L1 and MUC-1 expression were enrolled. CAR-NK cells were infused (1×109 cells/time) into these patients. Of 13 patients, 3 patients were withdrawn, 9 patients (69.2%) showed stable disease and 1 patient showed progressive disease. The cytokine level and hematologic changes were monitored to evaluate the safety. Severe cytokine storm and/or bone marrow suppression were not observed. From this phase I clinical trial we found that CAR-NK therapy has a broad prospect of application as a new cellular immunotherapy due to its stable clinical efficacy, mild side effects and ease of preparation. Citation Format: Qiao Li, Yi Wang, Ming Lin, Leiming Xia, Yangyi Bao, Xiang Sun, Lin Yang. Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A014.
BackgroundThe main purpose of this study was to explore the antitumor effect and mechanisms of ACAT1 inhibitor combined with CSCs-DC vaccine.Material/MethodsWe isolated HNSCC CSCs and gained CSCs antigens, then used CSCs antigens to load dendritic cells (DC) and generated a CSCs-DC vaccine. We treated mice after surgical excision of established SCC7 tumors with CSCs-DC vaccine and/or ACAT1 inhibitor, and recorded local tumor relapse and host survival. T cells and B cells were harvested from mice treated with CSCs-DC vaccine and/or ACAT1 inhibitor. We tested antibody production and the death rate of CSCs killed by T cells.ResultsThe tumors in the combined treatment group were smaller than in all other groups (P<0.01). The average survival time of the combined treatment group was 82 days and was the longest of all groups. Analysis of IgG levels secreted by B cell and CTL activity in spleens of mice found that results of the combined treatment group were the highest, and the results of the CSCs-DC group were lower than in the combined treatment group. The ACAT1 inhibitor group results were lower than in the CSCs-DC group and the combined treatment group results, but higher than in the PBS group, and the difference was statistically significant.ConclusionsACAT1 inhibitor enhanced the therapeutic effect of CSCs-DC vaccine in the treatment of the mouse HNSCC postoperative recurrence model. ACAT1 may play an important role in cancer immunotherapy.
Background: miR-100 has been reported to closely associate with gastric cancer (GC) initiation and progression. However, the underlying mechanism of miR-100-3p in GC is still largely unclear. In this study, we intend to study how miR-100-3p regulates GC malignancy. Methods: The expression levels of miR-100-3p in vitro (GES-1 and GC cell lines) and in vivo (cancerous and normal gastric tissues) were examined by quantitative real-time PCR (qRT-PCR). MTT and PE/Annexin V analyses were responsible for measurement of the effects of miR-100-3p on GC cell proliferation and apoptosis. Transwell assay with or without matrigel was used to examine the capacity of migration and invasion in GC cells. The interaction of miR-100-3p with bone morphogenetic protein receptor 2 (BMPR2) was confirmed through transcriptomics analysis and luciferase reporter assay. qRT-PCR and Western blot analyses were applied to determine the expression of ERK/AKT and Bax/Bcl2/Caspase3, which were responsible for the dysfunction of miR-100-3p. Results: miR-100-3p was down-regulated in GC cell lines and cancerous tissues, and was negatively correlated with BMPR2. Loss of miR-100-3p promoted tumor growth and BMPR2 expression. Consistently, the effects of miR-100-3p inhibition on GC cells were partially neutralized by knockdown of BMPR2. Over-expression of miR-100-3p simultaneously inhibited tumor growth and down-regulated BMPR2 expression. Consistently, over-expression of BMPR2 partially neutralized the effects of miR-100-3p over-expression. Further study demonstrated that BMPR2 mediated the effects downstream of miR-100-3p, which might indirectly regulate ERK/AKT and Bax/Bcl2/Caspase3 signaling pathways. Conclusion: miR-100-3p acted as a tumor-suppressor miRNA that down-regulated BMPR2, which consequently inhibited the ERK/AKT signaling and activated Bax/Bcl2/Caspase3 signaling. This finding provided novel insights into GC and could contribute to identify a new diagnostic and therapeutic target.
Objective: We aimed to investigate the expression of interleukin 12 (IL-12) family cytokines (IL-12, IL-23, IL-27 and IL-35) and their relevant cytokines (IFN-γ, IL-4, IL-17A and IL-10) in patients with chronic immune thrombocytopenia (cITP) as well as the effect of high-dose dexamethasone (HD-DXM) treatment on this expression. Materials and Methods: DXM was administered orally at a dose of 40 mg per day for 4 consecutive days to 38 patients with cITP. We measured the plasma levels of IL-12p70, IL-23, IL-27, IFN-γ, IL-4 and IL-17A before and after treatment and also in 36 matched healthy controls, by means of FlowCytomix™ technology. The plasma levels of IL-10 and IL-35 were measured by enzyme-linked immunosorbent assay. Results: Significantly higher plasma levels of IL-12p70, IL-23, IL-27, IFN-γ and IL-17A were observed in cITP patients than in controls (p < 0.01), and after HD-DXM treatment, these levels decreased significantly (p < 0.01). However, significantly lower plasma levels of IL-4, IL-10 and IL-35 were observed in cITP patients than in controls (p < 0.01); after the HD-DXM treatment, these levels had increased significantly in the cITP patients (p < 0.01). Moreover, the cytokine levels of patients who attained a complete response returned to the levels of normal controls (p > 0.05) but were not corrected in the patients who had no response (p < 0.01). Conclusions: The patients with cITP had abnormal expression of the IL-12 family cytokines and their relevant cytokines levels, and HD-DXM treatment corrected the derangement of plasma cytokines. Measuring cytokine levels may help in the clinical assessment of cITP.
Background: Volatile anesthetic-induced agitation, also called paradoxical excitation, is not uncommon during anesthesia induction. Clinically, patients with agitation may lead to self-injury or disrupt the operative position, increasing the incidence of perioperative adverse events. The study was designed to investigate clinical features of sevoflurane-induced agitation and examined whether any gene polymorphisms can potentially be used to predict agitation.Methods: One hundred seventy-six patients underwent anesthesia induction with sevoflurane were included in this study. Frontal electroencephalogram (EEG), electromyography (EMG), and hemodynamics were recorded continuously during anesthesia induction. DNA samples were genotyped using the Illumina Infinium Asian Screening Array and the SNaPshot technology. Genetic association was analyzed by genome-wide association study. Logistic regression analysis was used to determine the role of variables in the prediction of agitation.Results: Twenty-five (14.2%) patients experienced agitation. The depth of anesthesia index (Ai index) (p < 0.001), EMG (p < 0.001), heart rate (HR) (p < 0.001), and mean arterial pressure (MAP) (p < 0.001) rapidly increased during the agitation. EEG exhibited a shift toward high frequencies with spikes during agitation. The fast waves (alpha and beta) were more pronounced and the slow rhythms (delta) were less prominent during the occurrence of agitation. Moreover, three SNPs in the methionine synthase reductase (MTRR) gene were correlated to the susceptibility to agitation (p < 5.0 × 10−6). Carrying rs1801394 A > G (odds ratio 3.50, 95% CI 1.43–9.45) and/or rs2307116 G > A (3.31, 1.36–8.95) predicted a higher risk of agitation.Discussion: This study suggests that the agitation/paradoxical excitation induced by sevoflurane is characterized as increases in Ai index, EMG, HR and MAP, and the high frequency with spikes in EEG. Moreover, our results provide preliminary evidence for MTRR genetic polymorphisms, involving folate metabolism function, may be related to the susceptibility to agitation.Clinical Trial Number and Registry URL: ChiCTR1900026218; http://www.chictr.org.cn/showproj.aspx?proj=40655.
Immune thrombocytopenia (ITP) is an acquired autoimmune disorder. Both impaired platelet production and T-cell-mediated effects play a role in ITP. A T-helper1 (Th1) polarization of the immune response and up-regulation of Th17 cells have been demonstrated in ITP patients. Interleukin (IL)-12 and IL-23 produced by antigen presenting cells are essential for inducing and sustaining Th1 and Th17 effector cells via different pathways. However, less is known with regard to the levels of expression and synthesis of these two cytokines in patients with ITP. This was determined in this study in 46 patients with ITP as well as in 22 healthy controls. Our results showed that an increased expression of IL-12 p40, IL-12 p35, and IL-23 p19 mRNA was observed in bone marrow mononuclear cells and peripheral blood mononuclear cells of patients with ITP compared with controls. Consequently, higher levels of IL-12 and IL-23 were also found in bone marrow plasma and peripheral blood plasma in patients with ITP than in controls. Afterwards, a markedly higher level of IL-12 and IL-23 in bone marrow plasma or peripheral blood plasma was found in patients with chronic ITP than in patients with acute ITP. Furthermore, the peripheral blood plasma levels of IL-12 and IL-23 were negative correlated with platelet counts in ITP patients. Therefore, the augmented expression of IL-12 and IL-23 in patients with ITP may play an important role in the pathogenesis of this disease.
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