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.