ISHL10 Abstract T007

Hodgkin Lymphoma infiltrating T cells: considering various means of tumor evasion

The cellular microenvironment in classical Hodgkin lymphoma (cHL) is dominated by a mixed infiltrate of inflammatory cells with typically only one or a few percent of Hodgkin and Reed/Sternberg (HRS) tumor cells. HRS cells orchestrate this infiltrate by the secretion of a multitude of chemokines and direct cell–cell interactions. T cells are usually the largest population of cells in the HL tissue, encompassing T helper (Th) cells, regulatory T (Treg) cells and cytotoxic T cells. Helper and regulatory T cells presumably provide essential survival signals for the HRS cells, and the regulatory T cells also play an important role in rescuing HRS cells from cellular immune response. Here, we investigate the significance of the cHL-specific T cell infiltrate in regard to its role in tumor evasion. Comparing the global gene expression profiles of T cells isolated from cHL lymph nodes (LN) and reactive human tonsils revealed substantial phenotypical differences. Performing gene expression profiling, the T cell compartment in the cHL microenvironment featured an activated, highly proliferative and yet immunosuppressive phenotype. However, the nature of the regulative phenotype in both cHL CD4+ T cell subsets (Th: CD25- and CD127+; Tregs: CD25+ and CD127-) differs to the corresponding tonsillar Treg subset that comprises a purer population of natural FOXP3+ T cells. The ability of HRS cells to induce suppressive T cells was analyzed with an in vitro model system using human CD4+ peripheral blood (PB) T cells that were co-cultured with cHL cell lines. Co-cultured, naive T cells displayed an induced, CD25+ subpopulation and upregulated levels of FOXP3, CTLA4 and IRF4. Moreover, the exposure to HRS cells caused a dampened Th1 specific immune response. As for specific means of tumor evasion, the purinergic pathway seems an attractive co-factor. In vitro observations support a HRS dependent generation of environmental adenosine. Additionally, we observed an increase expression of the surface molecules BTLA and CD200R in cHL-infiltrating T cell subsets. Regarding their corresponding binding partners, typically expressed on tumor cells, most cHL cell lines were positive for HVEM and CD200. Taken together, we provide a novel perspective on the complex HRS - T cells interaction, verify its immunosuppressive nature and provide further insights into various means of tumor evasion in cHL.