Natural TCRs targeting KRASG12V display fine specificity and sensitivity to human solid tumors

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• KRAS-mutant (KRASMUT) neoantigens are recognized, but T cell receptor (TCR) specificity is unclear.
• Understanding TCR responses to KRAS neoantigens is crucial for cancer immunotherapy.

Purpose of the Study:

• To investigate KRASMUT immunogenicity and characterize TCRs targeting KRASG12V.
• To evaluate the therapeutic potential of KRASG12V-specific TCRs in HLA-A3 superfamily alleles.

Main Methods:

• Phase 1 clinical vaccine trial targeting KRASMUT.
• Isolation and comprehensive analysis of KRASG12V-specific TCRs (specificity, affinity, crossreactivity, CD8 dependence).
• Evaluation of TCR lytic activity and target antigen density via quantitative immunopeptidomics.

Main Results:

• Vaccination induced CD8+ and CD4+ T cell responses against KRASMUT.
• KRASG12V-specific TCRs showed high specificity for mutated protein, with no KRASWT reactivity.
• Both HLA-A*03:01 and HLA-A*11:01-restricted TCRs demonstrated potent anti-cancer lytic activity, with some CD4+ TCRs showing effector functions.

Conclusions:

• KRASG12V-specific TCRs possess high therapeutic potential for TCR-T cell therapy development.
• The identified TCRs are sensitive to low antigen levels, suggesting efficacy in diverse tumor settings.