TIPE2 (Tumor necrosis factor-α-inducible protein 8-like 2) is an emerging immune checkpoint molecule for NK cell maturation and antitumor immunity. TIPE2, encoded by TNFAIP8L, is a negative regulator of innate and adaptive immunity that is essential for immunological homeostasis. TIPE2 suppresses anti-tumor immune responses, increases macrophage differentiation into immunosuppressive M2 macrophages, and is necessary for CD4+CD25+ Treg cells to act immunosuppressively. Furthermore, TIPE2 has a significant impact on the differentiation and function of immunosuppressive leukocytes.
The highest levels of TIPE2 expression are seen in hematopoietic-related tissues/organs, particularly the spleen and lymph nodes. TIPE2 expression is increased in Hofbauer and Kupffer cells, as well as NK cells, macrophages, and monocytes. The top hematopoietic immune cells with the highest amount of TIPE2 expression are myeloid dendritic cells and monocytes. The immune cell infiltration is closely linked to TIPE2 expression, which is positively correlated with B-cell, CD4+ T-cell, neutrophil, macrophage, and dendritic cell infiltration levels, and partially negatively correlated with CD8+ T-cells.
TIPE2 expression is high in most cancers and is closely related to tumor development. Survival analysis revealed that TIPE2 expression is predictive of increased survival in cervical-squamous-cell-carcinoma (CESC), sarcoma (SARC), and skin-cutaneous-melanoma (SKCM). TIPE2 expression, on the other hand, indicates poorer survival in acute myeloid leukemia (LAML), lower-grade glioma (LGG), and kidney-renal-clear-cell-carcinoma (KIRC).
Figure 1 TIPE2 expression in cancers from TCGA and the GETx database1.
TIPE2 protein expression is found to be associated with NK cell maturation and to operate as a negative regulator, inhibiting NK cell development. TIPE2 deletion in NK cells increases the number of mature NK cells with enhanced effector capabilities and reaction to IL-15 stimulation through increased IL-15-triggered mTOR activity. As a result, NK-specific TIPE2-deficient cells may boost antitumor actions and become more resistant to tumor troubles.
Figure 2 TIPE2 expression in mice and humans correlates with NK cell maturation2.
TIPE2 may be a unique immune checkpoint biomarker across tumor types, with additional potential as an immunotherapy target. By targeting TIPE2, researchers aim to enhance anti-tumor immune responses and overcome immune suppression within the tumor microenvironment. Developing drugs that modulate TIPE2 activity holds promise for cancer immunotherapy.
TIPE2 expression is linked to a poor prognosis in many forms of cancer, suggesting that TIPE2 inhibitors may have a synergistic therapeutic effect in these tumors. Similar to other immune checkpoint molecules, combination therapies involving TIPE2 modulation might be necessary for optimal therapeutic efficacy. Combinations with immune checkpoint inhibitors (such as anti-PD-1/PD-L1 antibodies), chemotherapy, or targeted therapy could potentially enhance anti-tumor immune responses and improve treatment outcomes.
Targeting TIPE2 presents an opportunity for drug development in cancer immunotherapy. A great diversity of TIPE2 immunological checkpoint services is now available at Creative Biolabs, including but not limited to:
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