Identification and affinity enhancement of T-cell receptor targeting a KRASG12V cancer neoantigen
Mengyu Zhang1, Wei Xu2,3, Lingjie Luo4
1Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China.
Abstract:
Neoantigens derived from somatic mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), the most frequently mutated oncogene, represent promising targets for cancer immunotherapy. Recent research highlights the potential role of human leukocyte antigen (HLA) allele A*11:01 in presenting these altered KRAS variants to the immune system. In this study, we successfully generate and identify murine T-cell receptors (TCRs) that specifically recognize KRAS8-16G12V from three predicted high affinity peptides. By determining the structure of the tumor-specific 4TCR2 bound to KRASG12V-HLA-A*11:01, we conduct structure-based design to create and evaluate TCR variants with markedly enhanced affinity, up to 15.8-fold. This high-affinity TCR mutant, which involved only two amino acid substitutions, display minimal conformational alterations while maintaining a high degree of specificity for the KRASG12V peptide. Our research unveils the molecular mechanisms governing TCR recognition towards KRASG12V neoantigen and yields a range of affinity-enhanced TCR mutants with significant potential for immunotherapy strategies targeting tumors harboring the KRASG12V mutation.
Insights
Researchers engineered T-cell receptors (TCRs) to target KRAS G12V neoantigens, crucial for cancer immunotherapy. Enhanced TCR variants show higher affinity for KRAS G12V-HLA-A*11:01, offering new treatment strategies.
Area of Science:
- Oncology
- Immunology
- Structural Biology
Background:
- Somatic mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) are common in cancers.
- KRAS neoantigens presented by human leukocyte antigen (HLA) allele A*11:01 are potential immunotherapy targets.
Purpose of the Study:
- To generate and characterize T-cell receptors (TCRs) recognizing KRAS G12V neoantigens.
- To enhance TCR affinity for KRAS G12V-HLA-A*11:01 complexes through structure-based design.
Main Methods:
- Generation and identification of murine TCRs specific for KRAS G12V.
- Determination of the crystal structure of a TCR-peptide-HLA complex.
- Structure-based design and evaluation of affinity-enhanced TCR variants.
Main Results:
- Successfully generated TCRs that specifically recognize KRAS G12V neoantigen.
- Determined the structure of a TCR bound to KRAS G12V-HLA-A*11:01.
- Developed TCR variants with up to 15.8-fold increased affinity through two amino acid substitutions, maintaining specificity.
Conclusions:
- Elucidated molecular mechanisms of TCR recognition for KRAS G12V neoantigen.
- Developed high-affinity TCR mutants with potential for KRAS G12V-driven cancer immunotherapy.
- The engineered TCRs demonstrate promise for developing targeted cancer immunotherapies.
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