Increased interleukin-17A levels promote rituximab resistance by suppressing p53 expression and predict an unfavorable prognosis in patients with diffuse large B cell lymphoma

Abstract

Rituximab resistance has become increasingly common in patients with diffuse large B cell lymphoma (DLBCL). However, the mechanisms involved remain unclear. In this study, we aimed to examine the effect of rituximab on interleukin (IL)-17A and to investigate the role of IL-17A in rituximab resistance and its prognostic value in patients with DLBCL. Our retrospective analysis revealed that rituximab increased IL-6 expression levels in patients with DLBCL, and the increased IL-6 levels in turn induced the differentiation of Th17 and IL-17+Foxp3+ Treg cells, which secreted IL-17A both in vivo and in vitro. We then examined the effects of IL-17A on the apoptosis and proliferation of, and p53 expression in DLBCL cells, and found that IL-17A prevented rituximab-induced apoptosis and promoted the proliferation of DLBCL cells by suppressing p53 expression in vitro. The survival data of 73 patients with DLBCL suggested that high peripheral blood levels of IL-17A predicted an unfavorable survival. On the whole, our data indicate that rituximab promotes Th17 and IL-17+Foxp3+ Treg cells to secrete IL-17A, which in turn promotes rituximab resistance, partially by suppressing p53 expression and inhibiting rituximab-induced DLBCL cell apoptosis. IL-17A may thus prove to be a useful prognostic marker in patients with DLBCL.

IL-17 and colorectal cancer risk in the Middle East: gene polymorphisms and expression

“…49 Higher levels of IL-17A promotes rituximab resistance and serves as useful prognostic marker predicting unfavorable survival in patients with diffuse large B-cell lymphoma. 50 Recently, Zhu et al demonstrated that andrographolide, an anti-inflammatory compound isolated from Andrographis paniculata , can decrease the levels of IL-17A among other proinflammatory factors and suggested its therapeutic potential against ulcerative colitis. 51…”

A rationally-engineered IL-2 improves the antitumor effect of anti-CD20 therapy

“… 16 Contradictory results in the clinics have correlated the increase of Th17 with either a good 50 or a bad prognosis. 51 Interestingly, in B-NHL, we found that circulating Th17 frequencies in relapsed patients are significantly higher than those in untreated patients or normal individuals. 52 …”

“…16 Contradictory results in the clinics have correlated the increase of Th17 with either a good 50 or a bad prognosis. 51 Interestingly, in B-NHL, we found that Figure 7. No-alpha mutein maintains the long-lasting protection conferred by the anti-CD20 mAb.…”

B Cells versus T Cells in the Tumor Microenvironment of Malignant Lymphomas. Are the Lymphocytes Playing the Roles of Muhammad Ali versus George Foreman in Zaire 1974?

“…In classical B-cell lymphoma, circulating Th17 cells have a lower number in diagnosed patients versus healthy individuals. However, in B-cell lymphoma patients [47], it was proven that the Th17 cells sustain rituximab resistance [48], having a higher number in recurrent disease [47]. This may be caused by the fact that Th17 cells stimulate B-cell proliferation independent of B-cell normal or lymphomagenesis status.…”