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Cross talk between follicular helper T cells and tumor cells in human follicular lymphoma promotes immune evasion in the tumor microenvironment #MMPMID23686488
Rawal S; Chu F; Zhang M; Park HJ; Nattamai D; Kannan S; Sharma R; Delgado D; Chou T; Lin HY; Baladandayuthapani V; Luong A; Vega F; Fowler N; Dong C; Davis RE; Neelapu SS
J Immunol 2013[Jun]; 190 (12): 6681-93 PMID23686488show ga
The microenvironment of human follicular lymphoma (FL), an incurable B-cell non-Hodgkin lymphoma, is thought to play a major role in its pathogenesis and course. Microenvironmental cells of likely importance include follicular helper T cells (TFH) and regulatory T cells (Tregs), and understanding their interactions with FL tumor cells is necessary to develop novel therapeutic strategies. We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. IL-4 alone induces only CCL17, but enhances stimulation by CD40L of both CCL17 and CCL22. Consistent with our in vitro results, mRNA transcripts of IL-4 correlated with CCL17 but not CCL22 in gene expression profiling studies of FL biopsies, whereas CD40L correlated with both CCL17 and CCL22. Tumor supernatants induced preferential migration of Tregs and IL-4?producing T cells rather than IFN-??producing T cells, and antibodies to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4?producing T cells, which in turn may stimulate more chemokine production in a feed-forward cycle. Thus, TFH appear to play a major role in generating an immunosuppressive tumor microenvironment that promotes immune escape and tumor survival and growth. Our results provide novel insights into the cross talk between TFH, tumor cells, and Tregs in FL and offer potential targets for development of therapeutic strategies to overcome immune evasion.