TIPE2 specifies the functional polarization of myeloid-derived suppressor cells during tumorigenesis

Abstract

Myeloid-derived suppressor cells (MDSCs) are “polarized” myeloid cells that effectively promote tumorigenesis by inhibiting antitumor immunity. How myeloid cells acquire the protumoral properties during tumorigenesis is poorly understood. We report here that the polarity protein TIPE2 (tumor necrosis factor-α–induced protein 8-like 2) mediates the functional polarization of murine and human MDSCs by specifying their pro- and antitumoral properties. Tumor cells induced the expression of TIPE2 in Gr1+CD11b+ cells through reactive oxygen species (ROS). TIPE2 in turn increased the expression of protumoral mediators such as CCAAT/enhancer-binding protein-β while inhibiting the expression of antitumoral mediators. Consequently, tumor growth in TIPE2-deficient mice was significantly diminished, and TIPE2-deficient MDSCs markedly inhibited tumor growth upon adoptive transfer. Pharmaceutical blockade of ROS inhibited TIPE2 expression in MDSCs and reduced tumor growth in mice. These findings indicate that TIPE2 plays a key role in the functional polarization of MDSCs and represents a new therapeutic target for cancer immunotherapy.

Myeloid-Derived Suppressor Cells in Tumors: From Mechanisms to Antigen Specificity and Microenvironmental Regulation

“…These findings suggest a priming effect of tumor-derived pro-inflammatory cytokines. In a more recent study, tumor cells upregulate tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) in MDSCs through ROS, which in turn controls the polarization of MDSCs by increasing pro-tumoral and inhibiting anti-tumoral mediator expression ( 152 ).…”

Myeloid-Derived Suppressor Cell Differentiation in Cancer: Transcriptional Regulators and Enhanceosome-Mediated Mechanisms

“…High reactive oxygen species (ROS) associated within tumor microenvironments and IL-6 induce TIPE2 in myeloid precursors ( 30 , 31 ). Active TIPE2 promotes the expression of C/EBPß and STAT3 via the PI3K/AKT and MAPK/ERK pathways.…”

“…This leads to MDSC accumulation and polarization into an immunosuppressive phenotype. In the absence of TIPE2 MDSCs became anti-tumoral indicating TIPE2 functions as a molecular polarity switch in MDSCs ( 30 ). GCN2 similarly functions as a polarity switch in MDSCs.…”

“…As such, the identification of these drivers of pathological MDSC expansion and immunosuppressive activity has been the subject of intensive research in recent years. Recently identified MDSC effectors, mostly transcription factors (TFs) and apoptotic regulators, include IRF8 (23), STAT3 ( 23 – 26 ), C/EBPß ( 27 , 28 ), S100A8/9 ( 29 ), TIPE2 ( 30 , 31 ), GCN2 ( 32 ), among others ( Table 1 ). Of all these regulators, C/EBPß has emerged as an essential “master” regulator of MDSC expansion and immunosuppressive activity.…”

Tumor Necrosis Factor-α-Induced Protein 8-Like 2 Negatively Regulates Innate Immunity Against RNA Virus by Targeting RIG-I in Macrophages

“…Accelerating evidence indicates that TIPE2 inhibits the development of a variety of malignant tumors by suppressing cell proliferation ( 17 , 18 ), inducing cancer cell apoptosis ( 19 ), inhibiting tumor migration ( 20 , 21 ), and promoting antitumor immune responses mediated by CD8 + T and natural killer (NK) cells ( 22 ). TIPE2 has been recently shown to regulate the functional polarization of myeloid-derived suppressor cells (MDSCs) and maybe a potential therapeutic target for cancer immunotherapy ( 23 ). In addition, TIPE2 has been revealed to play a role in disrupting autophagy flux via RAC1-MTORC1 axis and impairing autophagic lysosome reformation ( 24 ).…”