Complex immune evasion strategies in classical Hodgkin lymphoma

The cellular microenvironment in classical Hodgkin lymphoma (cHL) is dominated by a mixed infiltrate of inflammatory cells with typically only about 1% Hodgkin and Reed/Sternberg (HRS) tumor cells. T cells are usually the largest population of cells in the cHL microenvironment, encompassing T helper (Th) cells, regulatory T (Treg) cells and cytotoxic T cells. Th and Treg cells presumably provide essential survival signals for HRS cells. Treg cells are also involved in rescuing HRS cells from anti-tumor immune responses. An understanding of the immune evasion strategies of HRS cells is not only highly relevant for a characterization of the pathophysiology of cHL, but also clinically, given the current treatment approaches targeting checkpoint inhibitors. Here, we characterized the cHL-specific CD4+ T cell infiltrate regarding its role in immune evasion. Global gene expression analysis of CD4+ Th and Treg cells isolated from cHL lymph nodes and reactive tonsils revealed that Treg cell signatures were enriched in CD4+ Th cells of cHL. Hence, HRS cells may induce a Treg differentiation in Th cells, which was supported by in vitro studies with Th cells and cHL cell lines. Furthermore, we found indication for immune-suppressive purinergic signaling and a role of the inhibitory receptor-ligand pairs BTLA-HVEM and CD200R-CD200 in promoting immune evasion. Taken together, this study reveals that the immune evasion strategies in cHL are even more complex and multifaceted than previously recognized.

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