Inhibition of Soluble Tumor Necrosis Factor Prevents Chemically Induced Carcinogenesis in Mice

Abstract

Tumor necrosis factor (TNF) is a potent promoter of carcinogenesis and potentially important target for cancer prevention. TNF is produced as functionally distinct transmembrane and soluble molecules (tmTNF and sTNF, respectively), but their individual roles in carcinogenesis are unexplored. We investigated the participation of tmTNF and sTNF in chemically induced carcinogenesis in mice. We found that injection of XPro1595, a dominant-negative TNF biologic (DN-TNF) and specific antagonist of sTNF, decreased tumor incidence and growth, and prolonged survival of 3-methylcholanthrene (MCA)-injected mice. Similar results were obtained following the exclusion of both TNF forms by either TNF-receptor 2–Fc fusion protein (TNFR2-Fc) treatment or TNF-gene deletion. In addition, gene-deletion of TNFR1, which is preferentially triggered by sTNF, temporarily blocked, whereas gene-deletion of TNFR2, which is preferentially triggered by tmTNF, enhanced MCA-induced carcinogenesis. Concomitantly with carcinogenesis induction, MCA increased circulating IL1α, accumulation of myeloid-derived suppressor-cells (MDSCs), STAT3 phosphorylation, and immunosuppression in the spleen. In sharp contrast, DN-TNF treatment dramatically decreased IL1α and increased the essential immunoregulatory cytokines IL1β, IL12p70, and IL17 in the peripheral blood of MCA-injected mice. In addition, MDSC accumulation, STAT3 phosphorylation, and immunosuppression in MCA-injected mice were prevented by DN-TNF treatment, TNFR2-Fc treatment, and/or gene deletion of TNF or TNFR1, but not deletion of TNFR2. These findings reveal that sTNF is both an essential promoter of carcinogenesis and a pivotal regulator of MDSCs; and indicate that sTNF could be a significant target for cancer prevention and therapy.

Immunogenomic analysis reveals LGALS1 contributes to the immune heterogeneity and immunosuppression in glioma

“…To investigate in detail how LGALS1 was involved in the GBM immunosuppressive microenvironment, we undertook big data analysis and evaluated the immunosuppressive cytokines known to be tightly associated with immunosuppressive microenvironment. LGASL1 was positively associated with immunosuppressive genes: LGALS3 , impairing function of human CD4 and CD8 tumour‐infiltrating lymphocytes, SWAP70 restricting spontaneous maturation of dendritic cells (DCs), CHI3L1 secreted by M2 macrophages promoting gastric and breast cancer metastasis, CCL2, SERPING1 inhibiting activation of the complement system, ANXA1 regulating TGF‐β signalling and promoting metastasis formation of basal‐like breast cancer cells, SHC1 promoting breast cancer immune suppression through STAT1 and STAT3, TIMP1 having a liner relationship with CD11b + Gr1+ myeloid cells and CD4 + CD25 + FOXP3+ Tregs, ICAM1 critical for mesenchymal stem cell (MSC)‐mediated immunosuppression, LTBP1 required for an adequate TGF‐β function, CD163, MR1 resulting in a relative increase in Tregs and TNFRSF1A required for STAT3 phosphorylation and MDSC accumulation . We also found that the expression of VEGFA, CCL2 and TGF‐β were restrained in the LGALS1 knockdown group.…”

T-cell–Secreted TNFα Induces Emergency Myelopoiesis and Myeloid-Derived Suppressor Cell Differentiation in Cancer

“…The soluble form of TNFa (sTNFa) mainly triggers TNFR-I, whereas the transmembranous form (tmTNFa) preferentially activates TNFR-II (50) with distinct biological functions. It has been documented that mainly sTNFa drives the differentiation and accumulation of MDSCs in a MCA tumor model (14). The function of TNFa in the regulation of hematopoiesis has been analyzed in different models with partially contradictory results: TNFa has been shown to suppress or increase the colony formation capacity of HSCs and their in vivo reconstitution capacity, probably depending on the dose and length of exposure studied (51,52).…”

“…Similarly, GM-CSF-secreted by mammary 4T1 tumors led to the expansion of myeloid progenitors and accumulation of CD11b þ GR-1 þ myeloid cells (12). In addition, TNFa has been shown to lead to the accumulation of MDSCs in murine and human tumors (13,14). Importantly, the vast majority of solid tumors do not secrete hematopoietic cytokines (8).…”

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

“…As mentioned before, TNFα is a major mediator of inflammation (59) with ambiguous effects and has been detected in human ovarian (60)(61)(62), breast (62,63), endometrial (62), oral (64), pancreatic (65), gastric (66), liver (67), prostate, bladder and colorectal (68) cancer as well as in lymphomas (69) and leukemias. It has been reported that knockout mice for TNFα are resistant to chemical-induced carcinogenesis (70)(71)(72). There has been quite a big controversy regarding TNFα expression as a parameter to predict clinical outcome in breast cancer patients (73)(74)(75)(76).…”