Loss of fragile site-associated tumor suppressor promotes antitumor immunity via macrophage polarization

Abstract

Common fragile sites (CFSs) are specific breakage-prone genomic regions and are present frequently in cancer cells. The (E2-independent) E3 ubiquitin-conjugating enzyme FATS (fragile site-associated tumor suppressor) has antitumor activity in cancer cells, but the function of FATS in immune cells is unknown. Here, we report a function of FATS in tumor development via regulation of tumor immunity. Fats−/− mice show reduced subcutaneous B16 melanoma and H7 pancreatic tumor growth compared with WT controls. The reduced tumor growth in Fats−/− mice is macrophage dependent and is associated with a phenotypic shift of macrophages within the tumor from tumor-promoting M2-like to antitumor M1-like macrophages. In addition, FATS deficiency promotes M1 polarization by stimulating and prolonging NF-κB activation by disrupting NF-κB/IκBα negative feedback loops and indirectly enhances both CD4+ T helper type 1 (Th1) and cytotoxic T lymphocyte (CTL) adaptive immune responses to promote tumor regression. Notably, transfer of Fats−/− macrophages protects mice against B16 melanoma. Together, these data suggest that FATS functions as an immune regulator and is a potential target in cancer immunotherapy.

TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection

“…To further confirm if the aforementioned influence of CFT073 wt on polarization of macrophages was caused by TcpC, rTcpC was prepared and its effects on macrophage polarization were also examined. In accordance with previous reports [ 27 , 31 , 32 ], LPS + IFN-γ significantly induced the expression of M1 markers CD80 and CD86, and IL-4 treatment promoted the expression of M2 markers CD163 and CD206 in both THP-1 and J774A.1 macrophage cell lines. However, 4 μg/mL rTcpC treatment profoundly attenuated LPS + IFN-γ=induced expression of CD80 and CD86 ( Figure 4 A–D), while promoting CD163 and CD206 expression ( Figure 4 E–H).…”

“…It was reported that complete polarization of macrophages to the M1 type requires activation of the MAPK and NF-κB signaling pathways [ 19 , 27 , 31 , 61 ], and M2 macrophage polarization requires activation of the STAT signaling pathway [ 62 , 63 ]. To explore the signal transduction pathways underlying the regulatory effects of TcpC on M1/M2 polarization, the influence of TcpC on MAPK/NF-κB and Akt/STAT pathways was examined.…”

“…THP-1 cells were treated with 100 nM phorbol-12-myristate-13-acetate (PMA) (Sigma, Saint Louis, MO, USA) for 24 h to induce cellular differentiation into macrophages [ 26 ]. LPS (100 ng /mL)/IFN-γ (20 ng/mL) and IL-4 (20 ng/mL) were added into the corresponding wells to stimulate M1 and M2 macrophage polarization [ 27 ]. Macrophage cell lines (THP-1 and J774A.1) were separately co-cultured in transwell with CFT073 wt or CFT073 ∆ tcpc at a multiplicity of infection (MOI) of 100 for 24 h. To examine the influence of TcpC on M1 and M2 macrophage polarization, 1 × 10 6 cells of THP-1 or J774A.1 were treated with or without 4 μg/mL rTcpC for 24 h. Supernatants were obtained for an ELISA assay and cells were collected for flow cytometry and qRT-PCR.…”

Protein Kinase C Delta Regulates Mononuclear Phagocytes and Hinders Response to Immunotherapy in Cancer

“…3A). In accordance with previous reports [40][41][42] , we observed that MP depletion significantly delayed tumor growth in wildtype mice (Prkcd +/+ ) (Fig. 3B,D).…”

Glutamine Metabolism-Regulated Nanoparticles to Enhance Chemoimmunotherapy by Increasing Antigen Presentation Efficiency

“…Unfortunately, M1 macrophages are in the minority while M2 macrophages are in the majority of tumors. M2 macrophages are involved in tumor invasion, metastasis, and immunosuppression in various manners to promote tumor growth and development. , At present, most studies have adopted various strategies to transform the formed M2-type into M1-type macrophages, − but these transformations are inefficient. Studies have revealed that the metabolic pathways of M2-type macrophages are reprogrammed in the process of maintaining their own vitality and function, such as highly dependent glutamine metabolism .…”