Limits...
TNF Neutralization Results in the Delay of Transplantable Tumor Growth and Reduced MDSC Accumulation.

Atretkhany KS, Nosenko MA, Gogoleva VS, Zvartsev RV, Qin Z, Nedospasov SA, Drutskaya MS - Front Immunol (2016)

Bottom Line: Under the influence of inflammatory cytokines, these cells become MDSCs, acquire immunosuppressive phenotype, and accumulate in the affected tissue, as well as in the periphery.TNF is a critical factor for the induction, expansion, and suppressive activity of MDSCs.Both etanercept and infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma in hTNF KI mice, significantly reduced tumor volume, and also resulted in less accumulated MDSCs in the blood 3 weeks after tumor cell inoculation.

View Article: PubMed Central - PubMed

Affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia; Immunology Department, Faculty of Biology, Beloszersky Institue of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.

ABSTRACT
Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells (IMCs) that, under normal conditions, may differentiate into mature macrophages, granulocytes, and dendritic cells. However, under pathological conditions associated with inflammation, cancer, or infection, such differentiation is inhibited leading to IMC expansion. Under the influence of inflammatory cytokines, these cells become MDSCs, acquire immunosuppressive phenotype, and accumulate in the affected tissue, as well as in the periphery. Immune suppressive activity of MDSCs is partly due to upregulation of arginase 1, inducible nitric oxide synthase, and anti-inflammatory cytokines, such as IL-10 and TGF-β. These suppressive factors can enhance tumor growth by repressing T-cell-mediated anti-tumor responses. TNF is a critical factor for the induction, expansion, and suppressive activity of MDSCs. In this study, we evaluated the effects of systemic TNF ablation on tumor-induced expansion of MDSCs in vivo using TNF humanized (hTNF KI) mice. Both etanercept and infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma in hTNF KI mice, significantly reduced tumor volume, and also resulted in less accumulated MDSCs in the blood 3 weeks after tumor cell inoculation. Thus, our study uncovers anti-tumor effects of systemic TNF ablation in vivo.

No MeSH data available.


Related in: MedlinePlus

Dual role of TNF in cancer and MDSCs. (A) TNF as anti-cancer agent. High doses of exogenous TNF induce tumor necrosis (25). However, necrotizing effect of TNF is not due to cytotoxic killing of tumor cells but because of direct action of TNF on endothelial cells, which leads to significant destruction of tumor-associated vessels and tumor rejection (56). Furthermore, TNF is an important molecule for anti-tumor immunity by cytotoxic NK- and T-cells (57, 58). In patients, TNF alone is inefficient, but in combination with chemotherapy, it increases tissue concentration of chemotherapy drugs, through the increase of blood vessel permeability, and is used in isolated perfusion procedure for the sarcoma treatment of the limb (59). (B) TNF as a pro-tumorigenic molecule. Binding of TNF with TNFR on endothelial cells and cancer-associated fibroblasts leads to NFκB activation and upregulation of chemokines, adhesion molecules, growth factors, and pro-inflammatory cytokines, resulting in increased angiogenesis, inflammation, and recruitment of immune cells (60, 61). TNF through the same signals activates proliferation of tumor cells and induces the release of different factors by tumor cells, such as metalloproteinases and VEGF, resulting in angiogenesis and tumor niche remodeling (62). (C) TNF and MDSCs. TNF and other pro-inflammatory cytokines, produced by tumor cells and tumor microenvironment, sustain chronic inflammation (63). During chronic inflammation myeloid cells do not differentiate into mature macrophages, neutrophils, and dendritic cells but rather accumulate as immature cells with suppressive capacity, so-called MDSCs (1). TNF is crucial for MDSCs, due to its direct effects on myeloid cells (33–35). MDSCs suppress anti-tumor immunity driving tumor development (9). (D) Anti-TNF therapy. Neutralization of TNF by etanercept or infliximab may result in tumor delay, decrease of MDSC accumulation, inefficient T-cell suppression, and increase of cytotoxic T-cells.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4835443&req=5

Figure 5: Dual role of TNF in cancer and MDSCs. (A) TNF as anti-cancer agent. High doses of exogenous TNF induce tumor necrosis (25). However, necrotizing effect of TNF is not due to cytotoxic killing of tumor cells but because of direct action of TNF on endothelial cells, which leads to significant destruction of tumor-associated vessels and tumor rejection (56). Furthermore, TNF is an important molecule for anti-tumor immunity by cytotoxic NK- and T-cells (57, 58). In patients, TNF alone is inefficient, but in combination with chemotherapy, it increases tissue concentration of chemotherapy drugs, through the increase of blood vessel permeability, and is used in isolated perfusion procedure for the sarcoma treatment of the limb (59). (B) TNF as a pro-tumorigenic molecule. Binding of TNF with TNFR on endothelial cells and cancer-associated fibroblasts leads to NFκB activation and upregulation of chemokines, adhesion molecules, growth factors, and pro-inflammatory cytokines, resulting in increased angiogenesis, inflammation, and recruitment of immune cells (60, 61). TNF through the same signals activates proliferation of tumor cells and induces the release of different factors by tumor cells, such as metalloproteinases and VEGF, resulting in angiogenesis and tumor niche remodeling (62). (C) TNF and MDSCs. TNF and other pro-inflammatory cytokines, produced by tumor cells and tumor microenvironment, sustain chronic inflammation (63). During chronic inflammation myeloid cells do not differentiate into mature macrophages, neutrophils, and dendritic cells but rather accumulate as immature cells with suppressive capacity, so-called MDSCs (1). TNF is crucial for MDSCs, due to its direct effects on myeloid cells (33–35). MDSCs suppress anti-tumor immunity driving tumor development (9). (D) Anti-TNF therapy. Neutralization of TNF by etanercept or infliximab may result in tumor delay, decrease of MDSC accumulation, inefficient T-cell suppression, and increase of cytotoxic T-cells.

Mentions: The reasons for these contrasting effects of endogenous versus systemically administered TNF are not fully understood. It is known that hemorrhagic necrosis of tumors is not due to direct TNF cytotoxicity on tumor cells but rather due to acute effects on tumor vasculature that is a part of tumor microenvironment (53) (Figure 5A). It is generally believed that such acute activating effects of TNF are very fast and are mediated by TNFRI. On the other hand, local effects of endogenous TNF, released from tumor cells and from tumor microenvironment, may be local and long-lasting and they could be mediated by both TNF receptors, with TNF–TNFRII axis having a distinct role because it requires tmTNF and cell-to-cell contacts (54). The downstream effects of such signaling may lead to the expression of pro-inflammatory cytokines, chemokines, and adhesion molecules resulting in chronic inflammation – one of the hallmarks of cancer development (55) (Figure 5B). In addition to this, TNF promotes expansion of MDSCs, which have pro-tumorigenic role and also accumulate during chronic inflammation (32, 33, 35) (Figure 5C). As already discussed, TNF therapy has found only limited clinical application in cancer treatment, while anti-TNF therapy is widely used in the treatment of autoimmune diseases. Could such systemic and often long-term TNF blockade predispose autoimmune patients to cancer? Or on the contrary, could anti-cytokine therapy provide a protection against emerging tumors? These are types of questions that we want to address in animal models.


TNF Neutralization Results in the Delay of Transplantable Tumor Growth and Reduced MDSC Accumulation.

Atretkhany KS, Nosenko MA, Gogoleva VS, Zvartsev RV, Qin Z, Nedospasov SA, Drutskaya MS - Front Immunol (2016)

Dual role of TNF in cancer and MDSCs. (A) TNF as anti-cancer agent. High doses of exogenous TNF induce tumor necrosis (25). However, necrotizing effect of TNF is not due to cytotoxic killing of tumor cells but because of direct action of TNF on endothelial cells, which leads to significant destruction of tumor-associated vessels and tumor rejection (56). Furthermore, TNF is an important molecule for anti-tumor immunity by cytotoxic NK- and T-cells (57, 58). In patients, TNF alone is inefficient, but in combination with chemotherapy, it increases tissue concentration of chemotherapy drugs, through the increase of blood vessel permeability, and is used in isolated perfusion procedure for the sarcoma treatment of the limb (59). (B) TNF as a pro-tumorigenic molecule. Binding of TNF with TNFR on endothelial cells and cancer-associated fibroblasts leads to NFκB activation and upregulation of chemokines, adhesion molecules, growth factors, and pro-inflammatory cytokines, resulting in increased angiogenesis, inflammation, and recruitment of immune cells (60, 61). TNF through the same signals activates proliferation of tumor cells and induces the release of different factors by tumor cells, such as metalloproteinases and VEGF, resulting in angiogenesis and tumor niche remodeling (62). (C) TNF and MDSCs. TNF and other pro-inflammatory cytokines, produced by tumor cells and tumor microenvironment, sustain chronic inflammation (63). During chronic inflammation myeloid cells do not differentiate into mature macrophages, neutrophils, and dendritic cells but rather accumulate as immature cells with suppressive capacity, so-called MDSCs (1). TNF is crucial for MDSCs, due to its direct effects on myeloid cells (33–35). MDSCs suppress anti-tumor immunity driving tumor development (9). (D) Anti-TNF therapy. Neutralization of TNF by etanercept or infliximab may result in tumor delay, decrease of MDSC accumulation, inefficient T-cell suppression, and increase of cytotoxic T-cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835443&req=5

Figure 5: Dual role of TNF in cancer and MDSCs. (A) TNF as anti-cancer agent. High doses of exogenous TNF induce tumor necrosis (25). However, necrotizing effect of TNF is not due to cytotoxic killing of tumor cells but because of direct action of TNF on endothelial cells, which leads to significant destruction of tumor-associated vessels and tumor rejection (56). Furthermore, TNF is an important molecule for anti-tumor immunity by cytotoxic NK- and T-cells (57, 58). In patients, TNF alone is inefficient, but in combination with chemotherapy, it increases tissue concentration of chemotherapy drugs, through the increase of blood vessel permeability, and is used in isolated perfusion procedure for the sarcoma treatment of the limb (59). (B) TNF as a pro-tumorigenic molecule. Binding of TNF with TNFR on endothelial cells and cancer-associated fibroblasts leads to NFκB activation and upregulation of chemokines, adhesion molecules, growth factors, and pro-inflammatory cytokines, resulting in increased angiogenesis, inflammation, and recruitment of immune cells (60, 61). TNF through the same signals activates proliferation of tumor cells and induces the release of different factors by tumor cells, such as metalloproteinases and VEGF, resulting in angiogenesis and tumor niche remodeling (62). (C) TNF and MDSCs. TNF and other pro-inflammatory cytokines, produced by tumor cells and tumor microenvironment, sustain chronic inflammation (63). During chronic inflammation myeloid cells do not differentiate into mature macrophages, neutrophils, and dendritic cells but rather accumulate as immature cells with suppressive capacity, so-called MDSCs (1). TNF is crucial for MDSCs, due to its direct effects on myeloid cells (33–35). MDSCs suppress anti-tumor immunity driving tumor development (9). (D) Anti-TNF therapy. Neutralization of TNF by etanercept or infliximab may result in tumor delay, decrease of MDSC accumulation, inefficient T-cell suppression, and increase of cytotoxic T-cells.
Mentions: The reasons for these contrasting effects of endogenous versus systemically administered TNF are not fully understood. It is known that hemorrhagic necrosis of tumors is not due to direct TNF cytotoxicity on tumor cells but rather due to acute effects on tumor vasculature that is a part of tumor microenvironment (53) (Figure 5A). It is generally believed that such acute activating effects of TNF are very fast and are mediated by TNFRI. On the other hand, local effects of endogenous TNF, released from tumor cells and from tumor microenvironment, may be local and long-lasting and they could be mediated by both TNF receptors, with TNF–TNFRII axis having a distinct role because it requires tmTNF and cell-to-cell contacts (54). The downstream effects of such signaling may lead to the expression of pro-inflammatory cytokines, chemokines, and adhesion molecules resulting in chronic inflammation – one of the hallmarks of cancer development (55) (Figure 5B). In addition to this, TNF promotes expansion of MDSCs, which have pro-tumorigenic role and also accumulate during chronic inflammation (32, 33, 35) (Figure 5C). As already discussed, TNF therapy has found only limited clinical application in cancer treatment, while anti-TNF therapy is widely used in the treatment of autoimmune diseases. Could such systemic and often long-term TNF blockade predispose autoimmune patients to cancer? Or on the contrary, could anti-cytokine therapy provide a protection against emerging tumors? These are types of questions that we want to address in animal models.

Bottom Line: Under the influence of inflammatory cytokines, these cells become MDSCs, acquire immunosuppressive phenotype, and accumulate in the affected tissue, as well as in the periphery.TNF is a critical factor for the induction, expansion, and suppressive activity of MDSCs.Both etanercept and infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma in hTNF KI mice, significantly reduced tumor volume, and also resulted in less accumulated MDSCs in the blood 3 weeks after tumor cell inoculation.

View Article: PubMed Central - PubMed

Affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia; Immunology Department, Faculty of Biology, Beloszersky Institue of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.

ABSTRACT
Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells (IMCs) that, under normal conditions, may differentiate into mature macrophages, granulocytes, and dendritic cells. However, under pathological conditions associated with inflammation, cancer, or infection, such differentiation is inhibited leading to IMC expansion. Under the influence of inflammatory cytokines, these cells become MDSCs, acquire immunosuppressive phenotype, and accumulate in the affected tissue, as well as in the periphery. Immune suppressive activity of MDSCs is partly due to upregulation of arginase 1, inducible nitric oxide synthase, and anti-inflammatory cytokines, such as IL-10 and TGF-β. These suppressive factors can enhance tumor growth by repressing T-cell-mediated anti-tumor responses. TNF is a critical factor for the induction, expansion, and suppressive activity of MDSCs. In this study, we evaluated the effects of systemic TNF ablation on tumor-induced expansion of MDSCs in vivo using TNF humanized (hTNF KI) mice. Both etanercept and infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma in hTNF KI mice, significantly reduced tumor volume, and also resulted in less accumulated MDSCs in the blood 3 weeks after tumor cell inoculation. Thus, our study uncovers anti-tumor effects of systemic TNF ablation in vivo.

No MeSH data available.


Related in: MedlinePlus