Cross Talk between Follicular Th Cells and Tumor Cells in Human Follicular Lymphoma Promotes Immune Evasion in the Tumor Microenvironment

Abstract

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-γ–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.

Activating STAT6 mutations in follicular lymphoma

“…[24][25][26][27][28] IL-4 levels are elevated in the FL microenvironment because of increased secretion by T follicular helper cells, and a fraction of FL cases harbor nuclear STAT6, indicative of activation. [29][30][31] To further our understanding of the genetic basis of FL and to identify targets for novel therapeutic approaches, we have performed massively parallel exome sequencing of 23 FL cases and one transformed FL (t-FL) case. Through subsequent validation of mutations in 2 expansion cohorts (a combined 114 FL cases), we identified novel STAT6 mutations in 11% of FLs.…”

IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

“…17 Moreover, IL-4 could indirectly contribute to the polarization and organization of the FL protumoral cell niche. In particular, IL-4 is a well-known inducer of dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin, a mannose-binding lectin recently implicated in the antigen-independent triggering of FL BCR by tumor-associated macrophages.…”

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

“…The binding sites of STAT6 have been found in the target regions of a variety of IL-4-mediated genes, including CD23 (Cooper et al, 2012), IL-4R (Jenkins et al, 2013), eotaxin-1 (Waddell et al, 2013), eotaxin-3 (Nakayama et al, 2010), FIZZ1 (Dasgupta et al, 2011), and in Ig germline e (Lu et al, 2007) promoters. Recently, IL-4-driven STAT6 constitutive activation has been found in various diseases, such as allergy (Hong et al, 2014), tumors (Cheah et al, 2014;Creytens et al, in press;Koelsche et al, 2014), and lymphoproliferative disorders (Rawal et al, 2013).…”