Functional coexpression of Interleukin (IL)‐7 and its receptor (IL‐7R) on Hodgkin and Reed‐Sternberg cells: Involvement of IL‐7 in tumor cell growth and microenvironmental interactions of Hodgkin's lymphoma

Abstract

The clinical and pathological features of classical Hodgkin lymphoma (cHL) mirror an abnormal tissue and systemic immune response due to the production of a variety of cytokines and chemokines by the malignant Hodgkin-Reed-Sternberg (H-RS) cells and/or surrounding reactive cells. Here, we demonstrate that HL-derived cell lines (L-428, KM-H2, HDLM-2, L-1236 and L-540) and primary H-RS cells from lymph node tissues of HL patients express the IL-7(R) receptor. IL-7 appears to be involved in autocrine circuitries of HL because L-1236, HDLM-2 and KM-H2 cells display the constitutive production of IL-7 and neutralizing anti-IL-7 antibodies induces a statistically significant inhibition of their basal proliferation. In addition, IL-7, either exogenous or fibroblasts-derived, promotes the clonogenic growth and reduces apoptosis of cultured H-RS cells, being also able to partially protect these cells from the cytotoxic effects of doxorubicin. We also provide evidence that IL-7 stimulates IL-6 secretion from IL-7R-expressing fibroblasts from HL-involved lymph nodes (HLFs), and that a striking increase in IL-6 secretion can be observed in cocultures of HLFs with L1236 cells. Finally, we show that L-1236 cells-derived IL-7 represents a costimulator for proliferation of purified CD4+CD25+CD127(dim/-) regulatory T cells (Tregs). Taken together, our data indicates that the IL-7/IL-7R axis constitutes an additional signaling pathway between H-RS cells and their reactive cellular background, thereby affecting proliferation and survival of tumor cells, acting as a cofactor for Tregs expansion and enhancing the microenviromental production of IL-6, a cytokine associated with the presence of "B" symptoms and a poor outcome in HL patients.