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Published on: October 25, 2016
Avidity optimization of a MAGE-A1-specific TCR with somatic hypermutation
David Bassan1, Yosi Meir Gozlan1, Adi Sharbi-Yunger1
1Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
A T-cell receptor (TCR) with optimal avidity to a tumor antigen can be used to redirect T cells to eradicate cancer cells via adoptive cell transfer. Cancer testis antigens (CTAs) are attractive targets because they are expressed in the testis, which is immune-privileged, and in the tumor. However, CTAs are self-antigens and natural TCRs to CTAs have low affinity/avidity due to central tolerance. We previously described a method of directed evolution of TCR avidity using somatic hypermutation. In this study, we made several improvements to this method and enhanced the avidity of the hT27 TCR, which is specific for the cancer testis antigen HLA-A2-MAGE-A1278-286 . We identified eight point mutations with varying degrees of improved avidity. Human T cells transduced with TCRs containing these mutations displayed enhanced tetramer binding, IFN-γ and IL2 production, and cytotoxicity. Most of the mutations have retained specificity, except for one mutant with extremely high avidity. We demonstrate that somatic hypermutation is capable of optimizing avidity of clinically relevant TCRs for immunotherapy.
Insights
This study enhanced T-cell receptor (TCR) avidity for cancer testis antigens (CTAs) using somatic hypermutation. Optimized TCRs improved T-cell cancer-killing ability in immunotherapy, demonstrating a viable strategy for cancer treatment.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Adoptive cell transfer using T-cell receptors (TCRs) can redirect T cells to eliminate cancer cells.
- Cancer testis antigens (CTAs) are promising targets due to their presence in tumors and immune-privileged testes.
- Natural TCRs targeting self-antigens like CTAs often exhibit low avidity due to central tolerance mechanisms.
Purpose of the Study:
- To improve the method of directed evolution of TCR avidity via somatic hypermutation.
- To enhance the avidity of the hT27 TCR, which targets the CTA HLA-A2-MAGE-A1278-286.
- To evaluate the impact of enhanced TCR avidity on T-cell function and specificity for cancer immunotherapy.
Main Methods:
- Utilized an improved directed evolution method based on somatic hypermutation to engineer TCRs.
- Introduced point mutations into the hT27 TCR to enhance its avidity for the target CTA.
- Transduced human T cells with engineered TCRs and assessed their binding, cytokine production, and cytotoxic activity.
Main Results:
- Identified eight point mutations that significantly improved TCR avidity.
- Engineered TCRs demonstrated enhanced binding to target antigen tetramers.
- Transduced T cells showed increased production of IFN-γ and IL2, and enhanced cytotoxicity against cancer cells.
- Most mutations maintained target specificity, with one mutant exhibiting exceptionally high avidity.
Conclusions:
- Somatic hypermutation is effective in optimizing TCR avidity for cancer immunotherapy.
- Enhanced TCR avidity translates to improved T-cell effector functions against tumors.
- This approach offers a promising strategy for developing more potent TCR-based cancer therapies.
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