Integrated T-Cell Receptor Repertoire and Tumor Immunogenicity Profiling Reveals Distinct Immunogenomic States in Endometrial Cancer
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Background
Endometrial cancer exhibits marked molecular and immune heterogeneity that is only partially explained by established genomic biomarkers. We investigated whether T-cell receptor (TCR) repertoire architecture captures complementary dimensions of antitumor immunity beyond conventional molecular classification.
Methods
Paired tumor and peripheral blood samples from eight patients with molecularly characterized endometrial cancer underwent TCR repertoire profiling. Diversity, clonality, and tumor–blood overlap metrics were integrated with genomic variables, including tumor mutational burden (TMB), genomic instability metric (GIM), and POLE status. Principal component analysis and correlation analyses were used to identify major dimensions of repertoire organization. Composite Immune Focusing and Immune Sharing Scores were derived to summarize dominant repertoire patterns.
Results
The first two principal components explained 70.1% of total repertoire variance and revealed substantial heterogeneity independent of histological subtype. TMB was strongly associated with reduced repertoire diversity and increased clonal dominance, resulting in a robust association with the Immune Focusing Score (ρ = 0.88, p = 0.004). POLE-mutated tumors occupied the extreme end of this focusing continuum. In contrast, genomic instability was associated with increased tumor–blood repertoire overlap and preserved diversity, reflected by a strong correlation between GIM and the Immune Sharing Score (ρ = 0.76, p = 0.027). The two immune scores showed minimal correlation with each other (ρ = −0.24, p = 0.57), indicating that they capture largely independent aspects of immune organization.
Conclusion
Integrative analysis of TCR repertoire architecture and tumor genomics identifies distinct immunogenomic states in endometrial cancer that are not fully captured by conventional molecular classification. If validated in larger cohorts, immune focusing and immune sharing metrics may provide complementary biomarkers for patient stratification and immunotherapy-oriented precision oncology.
