Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1

Abstract

Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.

Local application of bacteria improves safety ofSalmonella-mediated tumor therapy and retains advantages of systemic infection

“…TNF-α represents an important readout for the tumor therapeutic effects and a systemic response [ 35 , 54 , 55 ]. Hence, this cytokine was measured in serum upon infection with Salmonella .…”

Tumor Necrosis Factor Receptor-1 (p55) Deficiency Attenuates Tumor Growth and Intratumoral Angiogenesis and Stimulates CD8+ T Cell Function in Melanoma

“…Certainly, TNFR1 KO mice show more severe colitis-driven carcinogenesis compared to WT animals [ 13 ], which is probably related to enhanced inflammatory response. Moreover, pancreatic tumors are larger and more vascularized in TNFR1 KO than in WT mice [ 35 ]. Intriguingly, treatment of WT mice with human TNF-α, that only binds and activates murine TNFR1, increases pancreatic tumor growth [ 35 ].…”

“…Moreover, pancreatic tumors are larger and more vascularized in TNFR1 KO than in WT mice [ 35 ]. Intriguingly, treatment of WT mice with human TNF-α, that only binds and activates murine TNFR1, increases pancreatic tumor growth [ 35 ]. Therefore, engagement of TNFR1 may lead to either increased or decreased tumor growth.…”

The inflammatory milieu within the pancreatic cancer microenvironment correlates with clinicopathologic parameters, chemoresistance and survival

“…Potential environmental sequelae of pancreatitis such as hypoxia, the presence of reactive oxygen species, and acidosis may influence the development of PC [ 17 ]. Additionally, numerous soluble mediators, including TNF-α [ 18 ], TGF-α [ 19 ], TGF-β [ 20 ], IL-1β [ 21 ], IL-1α [ 22 ], IL-6 [ 23 , 24 ], IL-8 [ 25 ], VEGF [ 26 ], and others have been implicated in PC carcinogenesis, tumor progression, and treatment resistance. However, the relationship between the inflammatory milieu and the spectrum of disease from normal pancreas to pancreatitis to pancreatic cancer has not yet been characterized.…”