Soluble and Membrane-Bound TGF-β-Mediated Regulation of Intratumoral T Cell Differentiation and Function in B-Cell Non-Hodgkin Lymphoma

Abstract

While the effect of TGF-β on malignant B cells in non-Hodgkin lymphoma (NHL) has been previously evaluated, studies to specifically define the role of TGF-β in tumor immunity in B-cell NHL are limited. We found that soluble TGF-β, secreted by both lymphoma cells and intratumoral T cells, is present in the serum of patients with B-cell NHL. Soluble TGF-β promoted regulatory T (Treg) cells by enhancing expression of Foxp3 in CD4+ T cells and suppressed effector helper T (TH) cells by inhibiting expression of IFN-γ and IL-17. Blockade of the IL-2 signaling pathway diminished the effect of soluble TGF-β on T cell differentiation. Furthermore, we found that membrane-bound TGF-β is expressed specifically on the surface of malignant B cells in B-cell NHL. TGF-β was able to bind to the surface of lymphoma B cells through an interaction with heparan sulfate (HS) but not through the TGF-β receptor. We showed that pretreatment of lymphoma B cells with TGF-β significantly inhibits the proliferation and cytokine production of intratumoral T cells. Taken together, these results suggest that tumor-associated soluble and membrane-bound TGF-β are involved in the regulation of intratumoral T cell differentiation and function in B-cell NHL.

Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4+ T cells

“…Although receptor-mediated binding is usually the major mechanism of early signaling events, TGF-b can bind through other proteins such as biglycan or heparan sulfate as well. 35 We postulate that sGARP forms a LAP/TGF-b/ GARP complex and uses TGF-b signaling pathways, including these alternative receptors, that might be involved in sGARP function.…”

Involvement of transforming growth factor beta-1 (TGFβ1) cytokine and FOXP3 transcription factor genetic polymorphisms in hematological malignancies

“…Thus, TGFB1 polymorphism effect in HM development might be explained by the impairment in TGFβ1 secretion and the consequent decrement of cytostatic effects exerted by this cytokine directly in hematologic cells. It would also be interesting to evaluate a possible effect of this polymorphism during disease course, where TGFβ1 effects in anti-neoplastic immunological responses play important role (Yang et al 2013;Yang et al 2014), an issue that could not be assessed in this study due to limited and heterogeneous sample.…”

“…In hematological scenario, TGFβ1 is shown to be a potent inhibitor of hematopoiesis (Soderberg et al 2009;Blank and Karlsson 2011), inducing cell cycle arrest and apoptosis in normal and even in some malignant hematopoietic cells lineages (Tvrdik et al 2006;Wu et al 2009;Bakhshayesh et al 2012;Spender et al 2013). Nevertheless, it has been demonstrated that many hematological cells employ mechanisms to circumvent cytostatic and apoptotic effects of TGFβ1 (Dong and Blobe 2006), and, in this case, this cytokine is responsible to promote a immunosuppressive environment by suppressing effector T H cells and inducing naïve T cells to differentiate into regulatory T cells (Tregs) (Yang et al 2013), similarly to that which occurs in some solid tumors (Massague 2008;Yang et al 2010;Kubiczkova et al 2012). Tregs are major players in maintaining the immunological tolerance to self-antigens and in limiting the excessive and harmful immune responses.…”

Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies

“…113 Moreover, both IL-10 and TGF-b contribute to the selfmaintenance of the immunosuppressive environment by promoting the generation of induced Tregs. 114 Finally, VEGF, in addition to its proangiogenic effects, impairs DC maturation and directly inhibits T-cell proliferation and cytotoxic activity. 115 Besides cytokines, chemokines primarily contribute to the recruitment of inhibitory immune cells.…”