Intracellular Immune Checkpoint – PTP1B

Due to tumor heterogeneity and the complexity of the tumor microenvironment, immune checkpoint inhibitors are less efficient for treatment. The discovery of new immune checkpoint molecules or targets for co-immunotherapy is also a solution. Here Creative Biolabs introduces an intracellular immune checkpoint, Protein Tyrosine Phosphatase 1B (PTP1B), and gives some relevant information about its development and application.

New Inspiration for Immunotherapy Research

Immune checkpoint inhibitors are currently the most common immunotherapy regimen and have shown remarkable results in the treatment of melanoma, lung cancer and other tumors, such as PD-1 inhibitors and CTLA-4 inhibitors. The discovery of new immune checkpoint molecules or targets for co-immunotherapy has also been a hot research topic in recent years. However, the current research on immune checkpoints is mostly limited to the cell surface, and the existence of similar checkpoint molecules inside cells is still poorly understood. Focusing the attention on intracellular may give new inspiration for immunotherapy research.

Intracellular Immune Checkpoint - PTP1B

Protein Tyrosine Phosphatase (PTP) family is a class of intracellular phosphatases that, together with Protein Tyrosine Kinase (PTK), regulate a variety of intracellular signaling. PTP1B (encoding gene PTPN1) is an endoplasmic reticulum-localized phosphatase that is an important target for the treatment of metabolic diseases. It has been found that PTP1B can function as an intracellular immune checkpoint molecule.

Fig. 1 PTP1B acts as an intracellular checkpoint for T cell anti-cancer responses by blocking cytokine receptor signaling. (Salmond R J, 2022)

• High expression of PTP1B inhibits T cell proliferation and killing, which in turn promotes tumor growth.
• If PTP1B is knocked down, it will promote the activation of STAT5 signaling pathway in T cells, which in turn enhances T cell proliferation and killing power and inhibits tumor growth.
• PTP1B deletion or inhibition also promotes the effector function and infiltration of CAR-T cells into solid tumors, enhancing the inhibitory ability of CAR-T cells against solid tumors.
• PTP1B inhibitors in combination with other immune checkpoint inhibitors, such as PD-1 inhibitors, can exert superior effects than both alone.

PTP1B Inhibitors Development

The development of PTP1B inhibitors has been a subject of interest in academia and in the field of pharmaceutical research. Inhibition of PTP1B activity may have potential therapeutic benefits, particularly in metabolic disorders such as diabetes and obesity, as well as in modulating immune responses. Below are some strategies that can be used for PTP1B inhibitor development.

• High-throughput screening (HTS)
• 3D structure-based inhibitor design
• Natural products such as plant extracts and marine organisms
• Monoclonal antibody development
• In vitro functional assays

Potential Applications of PTP1B

• Cancer treatment. PTP1B inhibitors are being explored as potential anti-cancer agents. PTP1B inhibitors have been shown to have potential in inhibiting tumor growth and metastasis in various cancer types.
• Diabetes and insulin resistance therapy. By inhibiting PTP1B, insulin signaling can be enhanced, resulting in improved insulin sensitivity and glucose homeostasis.
• Obesity and weight control. PTP1B inhibitors may have implications for the treatment of obesity and weight control.

Taken together, intracellular immune checkpoints may also play a crucial role in regulating intracellular immune responses. Potential therapeutic targets for PTP1B have attracted interest. You can contact us to explore the complex role of targeting PTP1B in immune regulation and to evaluate its potential as a therapeutic target.

References

1. Salmond R J. Unleashing T cell responses to cancer through removal of intracellular checkpoints. Immunology and Cell Biology, 2022, 100(1): 18-20.
2. Wiede F, et al. PTP1B is an intracellular checkpoint that limits T-cell and CAR T-cell antitumor immunity. Cancer Discovery, 2022, 12(3): 752-773.

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