IL-9 contributes to immunosuppression mediated by regulatory T cells and mast cells in B-cell non-hodgkin's lymphoma.

It has been known that regulatory T (Treg) cells and mast cells (MCs) are involved in tumor immunity regulation, but the exact roles and mechanisms of Treg cells and MCs in B-cell non-Hodgkin's lymphoma (NHL) are incompletely defined. In the present study, we found that the number of Foxp3(+) Treg cells and CD117(+) MCs increased in B-cell NHL patients. Concomitantly, a high level of interleukin (IL)-9 was observed in the sera from B-cell NHL patients. Neutralizing IL-9 significantly inhibited tumor growth in the lymphoma model of murine, and this process was associated with down-regulation of Treg cells and MCs. Furthermore, IL-9 was also demonstrated to induce expression of MC-related genes and proliferation of MCs from the bone marrow stem cells. Collectively, our results indicate that Treg cell and MCs are involved in immunosuppression in B-cell NHL, and IL-9 is a key mediator of Treg cells and MCs in that process. These findings provide novel insight for the pathogenesis and possible therapeutic strategy of B-cell NHL.

Up-regulated expression of indoleamine 2,3-dioxygenase 1 in non-Hodgkin lymphoma correlates with increased regulatory T-cell infiltration.

Indoleamine 2,3-dioxygenase 1 (IDO1), which is a key enzyme in tryptophan metabolism expressed in some subsets of normal and neoplastic cells, participates in tumor-induced tolerance. However, the mechanisms involved are not clearly understood. A hypothesis suggests that IDO1 may be involved in proliferation and conversion of regulatory T cells (Tregs). In this study, we evaluated the levels of IDO1 and forkhead box P3 (FoxP3) in non-Hodgkin lymphoma (NHL) tissues and performed ex vivo experiments to investigate the role of IDO1 on T-cell tolerance in NHL. The results showed that expressions of IDO1 mRNA and protein were coincidentally higher in NHL tissues than in reactive hyperplasia of lymph node tissues. Up-regulation of IDO1 was correlated with later clinical phases, larger tumors and higher serum lactate dehydrogenase (LDH), and indicated a worse prognosis. FoxP3 mRNA and protein levels were markedly increased alongside elevated IDO1 levels. Co-culture of murine CD4 + CD25- T cells with A20 cells could initiate the conversion of CD4 + CD25+ T cells, which showed a suppressive function in the mixed lymphocyte reaction. Moreover, the potent inhibitor of IDO1, 1-methyl-l-tryptophan, attenuated the conversion of CD4 + CD25- T cells into CD4 + CD25+ FoxP3 + T cells. The results suggested that up-regulation of IDO1 in NHL tissues could induce local immune tolerance by favoring development and infiltration of FoxP3 + Tregs through the conversion of CD4 + CD25- T cells into CD4 + CD25+ FoxP3 + T cells in the tumor microenvironment. This could be a novel mechanism of NHL escape from immune control.

[Clinical significance of Livin expression in non-Hodgkin's lymphoma].

This study was aimed to explore clinical significance of Livin mRNA and protein expressions in non-Hodgkin's lymphoma (NHL). The immunohistochemistry was used to determine the expression of Livin protein in lymph nodes of 30 patients with NHL and 11 patients with reactive hyperplasia of lymph node. The real-time PCR was performed to detect the expression levels of Livin mRNA in 20 patients with NHL, 10 patients with reactive hyperplasia of lymph node and 4 normal person lymph nodes. The correlation of Livin mRNA and protein expressions with NHL clinical features were analyzed. The results showed that the expression of Livin mRNA was statistically higher in NHL samples than in normal lymph nodes and reactive hyperplastic lymph nodes (12.4 vs 0.34, 12.4 vs 0.61, median) (p<0.05), while there was no statistical difference between normal and reactive hyperplastic lymph nodes (p>0.05). Livin protein expression was exhibited to be positive in 16 of 30 cases of NHL with a positive rate of 53.3% and only 1 in reactive hyperplastic lymph nodes with a positive rate of 9.1%. In addition, Livin protein almost appeared in the cytoplasm of cells, seldom in nucleus. The expressions of both Livin mRNA and protein were positively correlated with clinical stages of NHL (p=0.023; p=0.009), B symptoms (p=0.015; p=0.026), blood beta2-microglobulin (beta2-MG, p=0.031; p=0.012) and the serum level of lactate dehydrogenase (LDH, p=0.037; p=0.007), but the expressions of Livin mRNA and protein had no significant correlation with age, sex and typing. It is concluded that the Livin mRNA and protein highly express in NHL patients and correlate with many clinical features, such as stage of NHL, B symptom, beta2-MG and LDH, therefore, the Livin may play a role in the prognosis of NHL patients. The further study on inhibitory effect of Livin expression will promote the illustration of NHL pathogenesis and contribute to the treatment and prognosis of NHL.