Spatial Transcriptomics and the mapping of T and B cell receptor sequences in human tissue

Session

Spatial and Imaging Cytometry

Authors

Dr Kim Thrane (1)

Affiliations

1. SciLifeLab, Department of Gene Technology, KTH Royal Institute of Technology

Keywords

Spatial VDJ, Spatial Transcriptomics, Spatially Resolved Transcriptomics, TCR, BCR, long-read sequencing

Abstract text

We developed Spatial Transcriptomics of VDJ sequences (Spatial VDJ), a method that detects and reveals the location of T and B cell clones in human tissue.

Spatially resolved transcriptomics has provided valuable insights into the gene expression dynamics of tissues, but current methods are typically restricted to detecting a predefined set of targets or sequencing a limited fraction of each transcript. The most widely adopted method is the Visium platform, based on transcriptome capture in thousands of 55µm-sized subareas (spots) of a tissue section. Although the Visium approach is unbiased in the sense that it can capture all polyadenylated RNAs, the downstream library preparation does not allow for the full-length transcript characterization essential for immune repertoire profiling.

T and B cell receptors can be produced in a myriad of combinations to specifically recognize and bind different types of antigens. Each naïve T and B cell expresses a unique receptor that is clonally inherited by its progeny, i.e. a clone. Sequencing antigen receptor transcripts can define clonality, but the most variable part of these transcripts, the CDR3 region, is lost in the standard short-read setup.

With Spatial VDJ, we generate spatially barcoded cDNA using the Visium platform. We then select T and B cell receptor transcripts using hybridization capture and perform long-read sequencing on the enriched material. Alongside, we generate a standard full gene expression sequencing library with short-read sequencing from the same tissue section to link clonal information to the transcriptional landscape.

Spatial VDJ captures thousands of unique T and B cell clones in human tonsil tissue with distributions matching T, B, and plasma cell markers, and uncovers B cell lineage trajectories in spatial context. Expanded clones are reproducibly detected across serial tissue sections, and their clonal sequences are confirmed by orthogonal methods. 

Spatial VDJ identifies B cell clones in breast cancer tissue that co-localize with different tumor-associates programs.

Taken together, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, which could have important therapeutic implications.