핵심 개념
Integrating T cell receptor beta chain (TCRβ) profiling data with peptide-HLA binding prediction improves the identification and prioritization of immunogenic neoantigens for personalized cancer immunotherapy.
초록
The study aimed to develop a novel workflow that integrates T cell receptor beta chain (TCRβ) sequencing data with peptide-HLA (pHLA) binding prediction to enhance the identification and prioritization of immunogenic neoantigens for personalized cancer immunotherapy.
Key highlights:
- TCRβ sequencing of tumor-infiltrating lymphocytes (TILs) from 27 colorectal cancer (CRC) patients revealed substantial intra-tumor and inter-patient heterogeneity in the TCRβ repertoire, likely due to the stochastic utilization of V and J segments in response to neoantigens.
- Analysis of publicly available datasets showed that both pHLA binding and pHLA-TCR binding strength are important determinants of neoantigen immunogenicity. Integrating these two features in a combined machine learning model improved the sensitivity and specificity for identifying immunogenic neoantigens compared to using either feature alone.
- Experimental validation using ELISpot assays on peripheral blood mononuclear cells (PBMCs) from 4 CRC patients confirmed that the combined model outperformed the conventional pHLA-based approach in selecting immunogenic neoantigen candidates.
- The study identified several novel neoantigen candidates with confirmed immunogenicity that were not previously reported in public databases, highlighting the potential of this integrated approach to uncover effective targets for personalized cancer immunotherapy.
통계
The TCRβ sequencing analysis yielded an average of 3,066,197 productive TCR reads per sample, with a range between 256,035 and 10,888,726.
Across the 27 patients, the number of TCRβ-CDR3 clonotypes ranged from 433 to 27,749, indicating substantial intra-tumor heterogeneity.
MSI-H tumors displayed a significantly lower number of TCRβ clonotypes compared to MSS tumors (2185 versus 6070, p=0.047).
인용구
"The recognition of the neoantigen-HLA complex through TCR is of paramount importance for T cell activation and eliciting an immune response."
"Sequencing the T cell receptors (TCRs) of TILs or lymphocytes found in peripheral blood provides crucial insights into the T-cell repertoire and their responses against neoantigens associated with tumors."
"The integration of both pHLA binding and pHLA-TCR binding strength features in our approach exhibited superior performance in neoantigen selection and prioritization when compared to the single-feature method."