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Stem Cell-Derived Viral Ag-Specific T Lymphocytes Suppress HBV Replication in Mice
Published on: September 25, 2019
Hepatitis C virus-cross-reactive TCR gene-modified T cells: a model for immunotherapy against diseases with genomic
Timothy T Spear1, Timothy P Riley2, Gretchen E Lyons3
1Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, Illinois, USA; tspear@luc.edu.
Abstract:
A major obstacle hindering the development of effective immunity against viral infections, their associated disease, and certain cancers is their inherent genomic instability. Accumulation of mutations can alter processing and presentation of antigens recognized by antibodies and T cells that can lead to immune escape variants. Use of an agent that can intrinsically combat rapidly mutating viral or cancer-associated antigens would be quite advantageous in developing effective immunity against such disease. We propose that T cells harboring cross-reactive TCRs could serve as a therapeutic agent in these instances. With the use of hepatitis C virus, known for its genomic instability as a model for mutated antigen recognition, we demonstrate cross-reactivity against immunogenic and mutagenic nonstructural protein 3:1406-1415 and nonstructural protein 3:1073-1081 epitopes in PBL-derived, TCR-gene-modified T cells. These single TCR-engineered T cells can CD8-independently recognize naturally occurring and epidemiologically relevant mutant variants. TCR-peptide MHC modeling data allow us to rationalize how TCR structural properties accommodate recognition of certain mutated epitopes and how these substitutions impact the requirement of CD8 affinity enhancement for recognition. A better understanding of such TCRs' promiscuous behavior may allow for exploitation of these properties to develop novel, adoptive T cell-based therapies for viral infections and cancers exhibiting similar genomic instability.
Insights
Genomic instability in viruses and cancers causes immune escape. Cross-reactive T cell receptors (TCRs) can recognize mutated antigens, offering a potential therapy for these challenging diseases.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Genomic instability in viral infections and cancers leads to immune escape through antigen mutations.
- Developing effective immunity against rapidly mutating pathogens and tumors remains a significant challenge.
Purpose of the Study:
- To investigate the potential of cross-reactive T cell receptors (TCRs) as a therapeutic strategy against mutating antigens.
- To demonstrate the efficacy of engineered T cells in recognizing and responding to viral mutations.
Main Methods:
- Utilized hepatitis C virus (HCV) as a model for studying mutated antigen recognition.
- Engineered T cells with specific TCRs to target viral epitopes.
- Employed TCR-peptide MHC modeling to analyze structural interactions and recognition mechanisms.
Main Results:
- Demonstrated cross-reactivity of engineered T cells against mutated nonstructural protein 3 (NS3) epitopes of HCV.
- Showcased CD8-independent recognition of naturally occurring and epidemiologically relevant mutant variants by engineered T cells.
- Provided molecular insights into how TCR structural properties accommodate mutated epitopes and influence CD8 dependence.
Conclusions:
- Cross-reactive TCRs offer a promising approach to overcome immune escape driven by antigen mutations in viral infections and cancers.
- Engineered T cells with specific TCRs can effectively target diverse mutant variants.
- Understanding TCR promiscuity can pave the way for novel adoptive T cell-based therapies for genomically unstable diseases.
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