High-sensitive spatially resolved T cell receptor sequencing with SPTCR-seq

• Published in: Nature communications Vol. 14; no. 1; pp. 7432 - 17
• Main Authors: Benotmane, Jasim Kada, Kueckelhaus, Jan, Will, Paulina, Zhang, Junyi, Ravi, Vidhya M., Joseph, Kevin, Sankowski, Roman, Beck, Jürgen, Lee-Chang, Catalina, Schnell, Oliver, Heiland, Dieter Henrik
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.11.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 38; 49; 49/39; 49/91; 631/1647/514/1949; 631/250/1619/554; 631/61/212/2019; 692/4028/67/1922; Cancer; Complementarity Determining Regions - genetics; Complementarity-determining region 3; Gene Expression Profiling; High-Throughput Nucleotide Sequencing - methods; Humanities and Social Sciences; Immunotherapy; Lymphocytes; Lymphocytes B; Lymphocytes T; multidisciplinary; Receptors; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell, alpha-beta - genetics; Science; Science (multidisciplinary); Spatial discrimination; Spatial resolution; T cell receptors; T-Lymphocytes; Transcriptomics; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-43201-6

Spatial resolution of the T cell repertoire is essential for deciphering cancer-associated immune dysfunction. Current spatially resolved transcriptomic technologies are unable to directly annotate T cell receptors (TCR). We present spatially resolved T cell receptor sequencing (SPTCR-seq), which integrates optimized target enrichment and long-read sequencing for highly sensitive TCR sequencing. The SPTCR computational pipeline achieves yield and coverage per TCR comparable to alternative single-cell TCR technologies. Our comparison of PCR-based and SPTCR-seq methods underscores SPTCR-seq’s superior ability to reconstruct the entire TCR architecture, including V, D, J regions and the complementarity-determining region 3 (CDR3). Employing SPTCR-seq, we assess local T cell diversity and clonal expansion across spatially discrete niches. Exploration of the reciprocal interaction of the tumor microenvironmental and T cells discloses the critical involvement of NK and B cells in T cell exhaustion. Integrating spatially resolved omics and TCR sequencing provides as a robust tool for exploring T cell dysfunction in cancers and beyond. Understanding T cell behaviour in cancers is vital for improving immunotherapies. Here, the authors present spatially resolved T cell receptor sequencing (SPTCR-seq), a technology that annotates T cell receptors within the tumour ecosystem.