Tumor necrosis factor receptor 2-dependent homeostasis of regulatory T cells as a player in TNF-induced experimental metastasis

Abstract

The cytokine tumor necrosis factor (TNF) has pleiotropic functions both in normal physiology and disease. TNF signals by the virtue of two cell surface receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Exogenous TNF promotes experimental metastasis in some models, yet the underlying mechanisms are poorly understood. To study the contribution of host TNFR1 and TNFR2 on tumor cell progression and metastasis, we employed a syngeneic B16F10 melanoma mouse model of lung metastasis combined with in vivo bioluminescence imaging. Treatment of tumor-bearing mice with recombinant human TNF resulted in a significant increase in tumor burden and metastatic foci. This correlated with an increase in pulmonary regulatory CD4(+)/Foxp3(+) T cells. TNF caused an expansion of regulatory T (Treg) cells in vitro in a TNFR2-dependent manner. To assess the contribution of immune cell expression of endogenous TNF and its two receptors on B16F10 metastasis, we generated bone marrow chimeras by reconstituting wild-type mice with bone marrow from different knockout mice. Loss of either TNF or TNFR2 on immune cells resulted in decreased B16F10 metastasis and lower numbers of Treg cells within the lungs of these animals. Selective depletion of Treg cells attenuated metastasis even in conjunction with TNF treatment. We propose a novel mechanism in which TNF activates TNFR2 on Treg cells and thereby expands this immunosuppressive immune cell population. Loss of either TNF or TNFR2 prevents the accumulation of Treg cells and results in a less tolerogenic environment, enabling the immune system to control B16F10 tumor metastasis and growth.

Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

“…We visualized the time course of Treg expansion in vivo using C57BL/6-FoxP3.Luci.DTR-4 mice that express the luc/gfp protein under control of the FoxP3 promoter. 24 Mice were treated with aDR3 or isotype mAb and the BLI signal emitted by expanding Tregs was significantly higher in aDR3-treated mice (Figure 1C-D; P , .0001 on days 4, 7, and 11, and P , .001 on day 18). The expanded Tregs persisted for 2 weeks and gradually contracted to the normal level.…”

“…Mice and cell line 24 Mice between the ages of 8 to 16 weeks were used and sex-matched combinations were used for transplant experiments. A20 and luc (derived from Balb/c mice) were used for GVT experiments.…”

Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma

“…Both B16 cell growth and tumor angiogenesis are reduced in TNF-R2-deficient mice (12). Moreover, lung invasion of intravenously injected B16 melanoma cells is decreased in TNF À/À and TNF-R2 À/À mice, indicating that TNF likely enhances melanoma dissemination in a TNF-R2-dependent manner (13). Vaccination toward TNF triggers self anti-TNF antibodies and inhibits lung invasion of intravenously injected B16 melanoma cells (14).…”

Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer

“…Moreover, persistently high autotaxin levels are linked to tumorigenesis and tumour progression in animal models of breast cancer, melanoma and glioblastoma (Jonkers & Moolenaar 2009, Altman et al 2010, Bhave et al 2013, Benesch et al 2014b, Venkatraman et al 2015. Cancers have been described as 'wounds that do not heal' (Dvorak 1986, Schafer & Werner 2008, Hanahan & Weinberg 2011, and inflammation is a hallmark of cancer progression , Germano et al 2008, Wu et al 2010, Chopra et al 2013, Grivennikov 2013. The role of individual cytokines such as IL1a, IL6 and IL17 has been documented in the growth of solid tumours such as pancreatic, gastric and colorectal cancers (Tjomsland et al 2013, Wang et al 2014, Li et al 2015.…”