High-affinity oligoclonal TCRs define effective adoptive T cell therapy targeting mutant KRAS-G12D.

Area of Science:

• Immunology
• Oncology
• Structural Biology

Background:

• Adoptive T cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) can cause cancer regression.
• Clinical application is limited by a low success rate.
• Understanding successful ACT cases is crucial for improving immunotherapy.

Purpose of the Study:

• Investigate a successful ACT case targeting KRAS-G12D mutated tumors.
• Characterize the T cell receptors (TCRs) and their neoantigen targets.
• Elucidate the structural basis of TCR-neoantigen-HLA interactions.

Main Methods:

• Analyzed TCRs from a patient with complete tumor regression.
• Identified KRAS-G12D neoantigens and their HLA-C*08:02 restriction.
• Determined TCR binding affinities and in vivo persistence.
• Resolved crystal structures of TCR-HLA-C complexes.

Main Results:

• Four TCRs recognized two KRAS-G12D neoantigens (nonamer and decamer) restricted by HLA-C*08:02.
• Mutant G12D peptides stabilized HLA-C*08:02 via a salt bridge.
• TCR affinities ranged from nanomolar to low micromolar and inversely correlated with in vivo persistence.
• Structural analysis revealed conserved TCR contacts and distinct neoantigen conformations, leading to an oligoclonal response.

Conclusions:

• Successful ACT involved high-affinity, oligoclonal TCRs recognizing distinct neoantigen conformations.
• Structural insights can guide immunotherapy development for KRAS-G12D tumors.
• This study has broad implications for T cell-based cancer immunotherapies.