- 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
investigators at the Medical University of South Carolina (MUSC).
Reason for Study
‘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.
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
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
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
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
- 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
"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
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
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.
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.
- 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,
- 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/)