Baohua Qian

Effect of interleukin 21 and its receptor on CD8+ T cells in the pathogenesis of diffuse large B-cell lymphoma

Interleukin 21 (IL-21) and its receptor, IL-21R, play a key role in innate and adaptive immunity. In the present study, the effect of IL-21 and IL-21R on the pathogenesis of diffuse large B-cell lymphoma (DLBCL) was investigated. The serum levels of IL-21 were detected by enzyme-linked immunosorbent assay, and the expression of IL-21R on CD8+ T cells was examined through flow cytometry. The data showed that the serum level of IL-21 was significantly decreased in the patients with DLBCL compared with the healthy controls (P<0.001), whereas the expression of IL-21R was clearly elevated on the CD8+ T cells in the patients with DLBCL. Further analyses revealed that the downregulation of the IL-21 serum level was correlated with an increased tumor stage of DLBCL, while the expression of IL-21R on the CD8+ T cells was positively correlated with the tumor stage. Also, the serum level of IL-21 and the proportion of IL-21R on the CD8+ T cells were negatively correlated in the patients. Notably, it was identified that the proportion of IL-21R on the CD8+ T cells, but not the serum level of IL-21, was significantly upregulated in the patients with bone-marrow involvement and B symptoms. These results indicate that IL-21 and IL-21R may be involved in the pathogenesis of DLBCL, in which IL-21R may reflect the progression of the disease more accurately than the serum level of IL-21.

Circulating CXCR5+CD4+ T cells assist in the survival and growth of primary diffuse large B cell lymphoma cells through interleukin 10 pathway

Abstract Diffuse large B cell lymphoma (DLBCL) is a common and aggressive cancer caused by the malignant transformation of B cells. Although it has been established that the follicular helper T (Tfh) cells play a central role in B cell development, little information is available on their involvement in DLBCL pathogenesis. We studied the role of the peripheral Tfh equivalent, the CXCR5+ CD4+ T cells, in DLBCL. Data showed that compared to CXCR5‐ CD4+ T cells, CXCR5+ CD4+ T cells were significantly more effective at promoting the proliferation as well as inhibiting the apoptosis of primary autologous DLBCL tumor cells. Surprisingly, we found that at equal cell numbers, CXCR5+ CD4+ T cells in DLBCL patients secreted significantly less interleukin (IL)‐21 than CXCR5‐ CD4+ T cells, while the level of IL‐10 secretion was significant elevated in the CXCR5+ compartment compared to the CXCR5‐ compartment. Neutralization of IL‐10 in the primary DLBCL‐CXCR5+ CD4+ T cell coculture compromised the CXCR5+ CD4+ T cell‐mediated pro‐tumor effects, in a manner that was dependent on the concentration of anti‐IL‐10 antibodies. The CXCR5+ compartment also contained significantly lower frequencies of cytotoxic CD4+ T cells than the CXCR5‐ compartment. In conclusion, our investigations discovered a previously unknown pro‐tumor role of CXCR5‐expressing circulating CD4+ T cells, which assisted the survival and proliferation of primary DLBCL cells through IL‐10. HighlightsWe studied the role of the peripheral Tfh in DLBCL.Tfh were effective at promoting the proliferation of primary DLBCL tumor cells.Tfh were effective at inhibiting the apoptosis of primary DLBCL tumor cells.IL‐10 secretion in Tfh was significant elevated in DLBCL.Neutralization of IL‐10 compromised Tfh‐mediated pro‐tumor effects.

Adaptive B cell responses in rituximab-treated diffuse large B cell lymphoma patients during complete remission

Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen. Treatment using rituximab in combination with chemotherapy has dramatically improved overall survival rate of diffuse large B cell lymphoma (DLBCL). Since rituximab can deplete both lymphoma B cells and normal B cells, how rituximab-treatment affects normal B cell function in DLBCL patients under remission is unclear. Here, we examined peripheral blood B cell composition and antigen-specific B cell responses in DLBCL patients in remission and observed reductions in the frequencies of total B cell as well as several major B cell subsets, including CD19+IgD+ naive B cells, CD19+IgD−CD27+ memory B cells, and CD19loCD27hi plasmablasts. Moreover, tetanus toxin (TT)-specific B cell proliferation was reduced in DLBCL patients in remission. On the other hand, HA-specific IgG-secreting B cell responses could be stimulated by influenza vaccination in DLBCL patients in remission, demonstrating that the machinery for generating de novo adaptive B cell responses was functional in DLBCL patients in remission. Our results provided insights in normal B cell function in DLBCL patients in remission.

The prevalence and function of CD4+CXCR5+Foxp3+ follicular regulatory T cells in diffuse large B cell lymphoma

&NA; CD4+CXCR5+Foxp3+ follicular regulatory T (Tfr) cells possess critical roles in suppressing the germinal center reaction, B cell activation, and follicular helper T cell (Tfh) cytokine secretion. Since diffuse large B cell lymphoma (DLBCL) can arise from B cells undergoing germinal center reaction and/or differentiation, we hypothesized that Tfr cells might be involved in DLBCL. In the present study, we recruited thirty‐five DLBCL patients and twenty‐five healthy controls. Data showed that DLBCL patients presented an enrichment of circulating CD4+CXCR5+Foxp3+ Tfr cells compared to controls. In the primary tumor isolated from enlarged lymph nodes, Tfr cells made up of roughly 3% to 16% of infiltrating T cells. Higher levels of tumor‐infiltrating Tfr cells were observed in patients with less advanced DLBCL stages, and in patients that stayed in remission 24 months after the initial R‐CHOP treatment. High BCL6 and high FOXP3 expression was observed in Tfr cells ex vivo. After anti‐CD3/CD28 and IL‐2 stimulation, the Tfr cells more closely resembled Treg cells and presented high IL10 and TGFB1 expression. CD4+CD25+CXCR5+ Tfr cells and CD4+CD25+CXCR5− non‐Tfr Treg cells could suppress CD4+CD25− Tconv cell and CD8+ T cell proliferation with similar capacity. However, Tfr cells were less capable of suppressing IFNG expression than Treg cells, and although both cell types supported CD19+ tumor cell proliferation, Tfr cells were less supportive than the non‐Tfr Treg cells. Overall, this study suggested that Tfr cells were involved in intratumoral immunity, were likely beneficial to DLBCL patients, and were functionally distinctive from non‐Tfr Treg cells. The distribution pattern and the prognostic value of Tfr cells in DLBCL should be examined in further studies. HighlightsThe frequency of Tfr cells was altered in the peripheral blood of DLBCL patients.Tumor‐infiltrating Tfr cells were lower in DLBCL patients with more advanced stages.Patients without relapsed disease had higher levels of intratumoral Tfr cells.Tfr cells were capable of mediating suppression of autologous T cell suppression.Tfr cells were less supportive in mediating CD19+ tumor cell proliferation.

Retraction Note to: Fibroblast growth factor receptor 4 polymorphisms and the prognosis of non-Hodgkin lymphoma

Fibroblast growth factors and their receptors (FGFRs) play important roles in blood system. FGFR4 rs351855 (Gly388Arg) polymorphism has shown to be a risk factor for many diseases. The aim of this study was to investigate the association between FGFR4 polymorphisms and the susceptibility to non-Hodgkin lymphoma (NHL) in the Chinese population. We identified two polymorphisms in the FGFR4 gene, rs351855G/A (Gly388Arg), and rs147603016G/A, by polymerase chain reaction-restriction fragment length polymorphism in 412 NHL cases and 476 healthy controls. Results showed that frequencies of AA genotype and A allele in rs351855 (Gly388Arg) polymorphism were significantly higher in patients than in controls (odds ratio (OR) 2.12, 95 % confidence intervals (CI) 1.99–3.48, P < 0.0001; OR 1.45, 95 % CI 1.21–1.88, P < 0.0001, respectively; data were adjusted for age and sex). The rs147603016G/A polymorphism did not show any correlation with NHL. When analyzing the survival time of NHL patients with FGFR4 rs351855G/A polymorphism, cases with AA genotype had significantly shorter survival time compared to the patients with GG and GA genotypes (P = 0.002). These results suggested polymorphism in FGFR4 gene was associated with increased susceptibility to NHL and could be used as a prognostic marker for this malignancy.

Effect of allogeneic blood transfusion on clinical outcomes of patients undergoing colorectal cancer surgery:a meta-analysis

Objective To evaluate the effects of allogeneic blood transfusion(ABT)on long-term prognosis in colorectal cancer(CRC)patients undergoing surgery.Methods PubMed,EMbase,The Cochrane Library and China Biology Medicine disc(CBMdisc)were searched for studies on the correlation between ABT and clinical outcomes of colorectal cancer patients,and relevant articles were also retrieved from references.All the searches were done from inception to March,2014.Two reviewers independently screened the literature,extracted the data and evaluated the quality of the data.Then the meta-analysis was performed by using Stata12.0software.Results Finally 8studies involving 5 479 patients were included.The results of metaanalysis showed that,compared with non-transfusion group,the transfusion group had significantly increased risks of overall survival(by 21%,HR=1.21;95% CI:1.09-1.33;P0.001)and disease-specific survival(by 47%,HR=1.47;95% CI:1.17-1.84;P=0.001);whereas the risks of disease free survival,local recurrence or distant metastasis were not significantly different between the 2groups.Conclusion ABT can increase the risks of overall survival and disease-specific survival in CRC patients undergoing surgery;therefore,it is of great clinical significance to take active perioperative blood conservation strategies to decrease ABT rate.