Novel Immunoregulatory Protein Could Be Potential Cancer Treatment Target

Inhibition of moesin, a novel protein that normally suppresses immune attack against tumor cells could become potential cancer treatment target.

Highlights:

Cytotoxic T cells are a subset of immune cells capable of killing cancer cells.
Generation of Tregs in the tumor microenvironment suppresses cytotoxic T-cell function and promotes tumor growth.
Moesin, a novel protein has been shown to enhance Tregs formation and favor cancer cell survival by escaping the immune system.
Moesin inhibitors could, therefore, become potential treatment option in cancer immunotherapy.

Moesin, a membrane-domain organizing protein, controls regulatory T cell (Treg) function and could be a potential therapeutic target for treatment, according to preclinical research by investigators at the Medical University of South Carolina (MUSC).

Reason for Study

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‘Moesin inhibitors prevent generation of regulatory T-cells or Tregs (that dampen immune response) and could be potential cancer treatment option.’

The search for cancer cure continues unabated and scientists toil tirelessly to find a cure for cancer.

One of the forms of cancer treatment is Immunotherapy which involves using agents that modulate the immune system. The current research endeavor hopes to develop one such agent that could target the tumor cells attempts at evading killing by the host cytotoxic T-cells.

How Moesin Suppresses the Immune T cells

Moesin is a membrane organizing protein and a member of the ERM protein family, whose other members are ezrin and radixin. Moesin is thought to play a role in cancer progression.

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Under normal circumstances, when an immune response is complete, a growth factor called transforming growth factor –β (TGF-β) acts to convert naïve T cells to Tregs which in turn suppress the activated inflammatory T cells and degrade them. This keeps the inflammatory response in check as an exaggerated immune response can be harmful to the host and also cause autoimmune diseases.

The protein enhances the role of TGF-β in the formation of Tregs. Thus moesin acts in tune with TGF-β to dampen the immune response.

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Analyzing the role of moesin in inhibiting the T-cells the research team noted the following results

Moesin increases Treg generation by interacting with a TGF-beta receptor (TβR-II) making it more abundant, and suppresses the activity of cytotoxic T-cells.
On the other hand, TGF-beta signaling was decreased in the absence of moesin, interfering with the generation and function of Tregs thereby enhancing the T-cell activity.

Results of Testing Adoptive T-Cell Therapy in Mice Lacking Moesin

The research team conducted further experiments to validate their above observation. To this end, they studied the results of using adoptive T-cell therapy in mice lacking moesin.

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In adoptive T cell therapy, tumor-killing cytotoxic T cells are "harvested" from a human or animal with cancer and amplified or otherwise "supercharged" and once again being re-infused back into the donor. These amplified T-cells are highly effective in killing tumor cells but their activity is short-lived giving scope for tumor recurrence.

When these anti-cancer T cells were injected into mice lacking moesin, these cells became activated and multiplied rapidly and survived for a longer period of time reducing incidence of tumor recurrence. Interestingly, all the mice with moesin relapsed, while most of the mice lacking moesin were cured of the tumor.

"When the mice lacking moesin had no recurrence, this was really exciting. We were not only deleting moesin but, when we gave T cells to the active tumors, those T cells could control the cancer for a very long time," explains Ephraim Ansa-Addo, Ph.D., a postdoctoral fellow in the Department of Microbiology and Immunology and lead author of the article.

How Tumor Cells Evade Immune T-Cells

Cancer cells have evolved mechanisms to hide from or avoid the tumor-killing T cells. Many cancer cells produce TGF-β which attaches to the surface of tumor-killing helper T cells preventing them from fighting the tumor cells. These T cells become converted to Tregs and depress the immune response against the tumor.

"Because moesin supports greater Treg production, we could design moesin inhibitors to halt or slow active TGF-beta signaling and slow down Treg conversion so that anti-tumor T cells can have a chance to see the cancer and eradicate it," explains Zihai Li, M.D., Ph.D., chair of the Department of Microbiology and Immunology at MUSC and senior author on the paper.

Conclusion

These findings of the study suggest that moesin could be a potential therapeutic target in developing new treatments for cancer as well as immune disorders. Inhibitors of moesin could be developed to treat cancers while moesin inducers may have the potential to treat autoimmune diseases. Moesin modulators could also be combined with current immunotherapy regimens.

"These findings are very interesting for the field and provide a lot of directions for further research into alternative therapies," says Li.

References:

Ephraim A. Ansa-Addo, Yongliang Zhang, Yi Yang, George S. Hussey, Breege V. Howley, Mohammad Salem, Brian Riesenberg, Shaoli Sun, Don C. Rockey, Serhan Karvar, Philip H. Howe, Bei Liu, Zihai Li. Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-尾 signaling. Journal of Clinical Investigation, (2017); DOI: 10.1172/JCI89281
Moesin - (https://en.wikipedia.org/wiki/Moesin)
Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling - (https://www.jci.org/articles/view/89281)
Ezrin-Radixin-Moesin family proteins in the regulation of B cell immune response - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548853/)

Source-Medindia