Prognostic impact of tumour-infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma.

Classical Hodgkin Lymphoma (cHL) is morphologically characterized by a small number of tumour cells, Hodgkin and Reed-Sternberg (HRS) cells, surrounded by numerous tumour-infiltrating lymphocytes (TIL). The functional role of these TIL is still controversial. While generally considered to represent an anti-tumour immune response, TIL in cHL might result from the profoundly deregulated immunity of cHL patients. Eighty-seven cases of cHL were available to evaluate the prognostical significance of tumour-infiltrating cytotoxic T lymphocytes (CTL), T helper 1 (Th1) cells, T helper 2 (Th2) cells and regulatory T cells (Treg). We confirm that in cHL the microenvironment is dominated by Th2 cells and Treg and show that large numbers of Th2 cells are associated with significantly improved disease-free survival (p = 0.021) and event-free survival (p = 0.012). Furthermore, a high ratio of Treg over Th2 cells resulted in a significantly shortened disease-free survival (p = 0.025). These observations suggest that Treg may exert inhibitory effects on anti-tumour immune responses mediated through Th2 cells and that Th2 cells may be more important for effective anti-tumour immunity than anticipated.

Expression of RANTES and MCP-1 in epithelial cells is regulated via LMP1 and CD40.

Epstein-Barr virus (EBV)-associated undifferentiated nasopharyngeal carcinoma (NPC) is characterized by a prominent nonneoplastic lymphoid stroma. The functional role of these inflammatory cells and the mechanism of their recruitment are not fully understood. In B-cells, the EBV-encoded latent membrane protein 1 (LMP1) can induce the expression of chemokines in an NF-kappaB dependent manner. We now show that LMP1 can induce the expression of RANTES and MCP-1 in an epithelial cell line, and that this effect is partially reversible by an inhibitor of NF-kappaB. Since tumor cells of virtually all NPCs show CD40 expression while many cases are LMP1-negative at the protein level, we also investigated the effect of CD40 signaling and demonstrate that CD40 stimulation can transiently induce RANTES and MCP-1 expression in LMP1-negative epithelial cells. In in situ hybridization only rare tumor cells showed expression of these chemokines unrelated to LMP1 expression, a pattern consistent with transient induction through CD40 signaling. Since RANTES and MCP-1 were also detected in the neoplastic cells of oral squamous cell carcinomas lacking a lymphoid stroma it remains uncertain to what extent these CC chemokines contribute to the attraction of inflammatory cells into the NPC microenvironment.