Investigation of antigen-specific T-cell receptor clusters in human cancers

Hongyi Zhang, Longchao Liu, Jian Zhang, Jiahui Chen, Jianfeng Ye, Sachet Shukla, Jian Qiao, Xiaowei Zhan, Hao Chen, Catherine J. Wu, Yang-Xin Fu, Bo Li

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Purpose: Cancer antigen-specific T cells are key components in antitumor immune response, yet their identification in the tumor microenvironment remains challenging, as most cancer antigens are unknown. Recent advance in immunology suggests that similar T-cell receptor (TCR) sequences can be clustered to infer shared antigen specificity. This study aims to identify antigen-specific TCRs from the tumor genomics sequencing data. Experimental Design: We used the TRUST (Tcr Repertoire Utilities for Solid Tissue) algorithm to assemble the TCR hypervariable CDR3 regions from 9,700 bulk tumor RNA-sequencing (RNA-seq) samples, and developed a computational method, iSMART, to group similar TCRs into antigen-specific clusters. Integrative analysis on the TCR clusters with multi-omics datasets was performed to profile cancer-associated T cells and to uncover novel cancer antigens. Results: Clustered TCRs are associated with signatures of T-cell activation after antigen encounter. We further elucidated the phenotypes of clustered T cells using single-cell RNA-seq data, which revealed a novel subset of tissue-resident memory T-cell population with elevated metabolic status. An exciting application of the TCR clusters is to identify novel cancer antigens, exemplified by our identification of a candidate cancer/testis gene, HSFX1, through integrated analysis of HLA alleles and genomics data. The target was further validated using vaccination of humanized HLA-A*02:01 mice and ELISpot assay. Finally, we showed that clustered tumor-infiltrating TCRs can differentiate patients with early-stage cancer from healthy donors, using blood TCR repertoire sequencing data, suggesting potential applications in noninvasive cancer detection. Conclusions: Our analysis on the antigen-specific TCR clusters provides a unique resource for alternative antigen discovery and biomarker identification for cancer immunotherapies.

Original languageEnglish (US)
Pages (from-to)1359-1371
Number of pages13
JournalClinical Cancer Research
Volume26
Issue number6
DOIs
StatePublished - Mar 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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