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T Cells Specific for an Unconventional Natural Antigen Fail to Recognize Leukemic Cells
Margot J Pont1,2, Rimke Oostvogels3, Cornelis A M van Bergen1
1Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
Cancer Immunology Research
|March 21, 2019
Summary
Researchers identified a novel T-cell epitope from the TTK gene in leukemia patients. This aberrant protein target, though recognized by T cells, was not effectively targeted in leukemic cells, highlighting challenges in cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Aberrant proteins on cancer cells present potential targets for immunotherapy.
- Identifying naturally occurring tumor-specific antigens is challenging.
- Nonsense-mediated decay (NMD) pathway can generate aberrant transcripts.
Purpose of the Study:
- To identify and characterize a naturally occurring T-cell epitope derived from an aberrant protein.
- To investigate the recognition of this epitope by T cells in leukemia patients.
- To explore the potential of targeting NMD-derived epitopes in cancer immunotherapy.
Main Methods:
- Identification of a T-cell epitope from an alternative TTK transcript.
- Analysis of T-cell recognition using HLA-A*02:01-restricted CD8+ T cells.
- Functional assays on leukemic cells expressing the alternative TTK transcript.
Main Results:
- A novel T-cell epitope was identified from a truncated TTK protein transcript.
- This epitope was recognized by CD8+ T cells from a leukemia patient.
- Leukemic cells expressing the aberrant transcript failed to be recognized by these T cells.
- Antigen processing and presentation mechanisms appeared intact.
Conclusions:
- Naturally occurring epitopes from aberrant proteins, like TTK, can be generated via alternative splicing and NMD.
- Leukemic cells may possess mechanisms to evade recognition of such aberrant antigens.
- Targeting NMD-derived or unconventionally generated epitopes in cancer immunotherapy may face significant hurdles.
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