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Published on: November 17, 2018
CD8 co-receptor modulates the specificity profile of the 1G4 TCR against NY-ESO-1
Heather F Jones1, Zita Aretz2, Ron S Gejman3
1Pharmacology Program, Weill Cornell Medicine, New York, NY 10021, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
Engineered T cells have shown efficacy in cancer treatment. However, the promiscuity of TCR-engineered T cells may result in recognition of off-target epitopes, causing severe toxicities. A genetic screen of >3,000 proteomic epitopes in the MHCI ligandome uncovered off-target peptides for both, native and affinity-enhanced 1G4 TCR, which target cancer antigen NY-ESO-1/A02-expressing cells. We validated off-target peptides derived from the human proteome recognized by both TCRs, showing that the affinity-enhanced TCR has more off-targets. Multiple off-target epitopes were reactive only in CD8 T cells, not in CD4 T cells. We identified a previously undescribed class of CD8 receptor-dependent off-targets. CD8α-negative cells (CD8α-/-) 1G4 T cells had fewer off-target reactivities, enhancing on-target specificity in vitro and in vivo. We corroborated our findings with the DMF5 TCR, targeting MART1/A02. This research advances our understanding of the distinct roles that CD4 and CD8 proteins play in T cell antigen recognition, potentially leading to more specific, effective, and safer engineered T cell therapies.
Insights
Engineered T cells show cancer treatment promise but can cause toxicity. This study identified off-target peptides recognized by T cell receptors (TCRs), revealing CD8 dependence and suggesting strategies for safer engineered T cell therapies.
Area of Science:
- Immunology
- Cancer Biology
- Genetic Engineering
Background:
- Engineered T cells, particularly T cell receptor (TCR)-engineered T cells, are effective cancer therapeutics.
- TCR promiscuity can lead to off-target epitope recognition, causing severe adverse effects.
- Understanding TCR specificity is crucial for developing safer and more effective cell therapies.
Purpose of the Study:
- To identify off-target peptides recognized by native and affinity-enhanced 1G4 TCRs targeting NY-ESO-1/A02.
- To investigate the role of CD4 and CD8 proteins in T cell antigen recognition by engineered T cells.
- To explore strategies for enhancing the specificity of TCR-engineered T cells.
Main Methods:
- Genetic screening of over 3,000 proteomic epitopes in the MHCI ligandome.
- Validation of off-target peptides using native and affinity-enhanced 1G4 TCRs.
- Testing T cell reactivity in CD8α-negative (CD8α-/-) cells and corroboration with DMF5 TCR targeting MART1/A02.
Main Results:
- Uncovered off-target peptides for both native and affinity-enhanced 1G4 TCRs, with the enhanced TCR exhibiting more off-target reactivities.
- Identified a novel class of CD8 receptor-dependent off-target epitopes.
- CD8α-/- 1G4 T cells demonstrated reduced off-target reactivity and enhanced specificity in vitro and in vivo.
- Findings were validated using the DMF5 TCR targeting MART1/A02.
Conclusions:
- Engineered T cell therapies face challenges with off-target toxicities due to TCR promiscuity.
- CD8 dependence plays a significant role in T cell antigen recognition, offering a target for improving specificity.
- Modulating CD8 interactions or utilizing CD8α-/- T cells may enhance the safety and efficacy of engineered T cell therapies.
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