Spatially mapping T cell receptors and transcriptomes

Abstract T cells mediate antigen-specific immune responses to disease through the specificity and diversity of their T-cell receptors (TCRs). Although determining the spatial distributions of T cell clonotypes in tissues is essential to understanding T cell maturation and behavior, spatial sequencing methods remain unable to profile the TCR repertoire. We have developed Slide-TCR-seq, a 10-μm-resolution method to sequence whole transcriptomes and TCRs within the spatial context of intact tissues. We first confirmed the ability of Slide-TCR-seq to map the characteristic architecture of T cells and their receptors in mouse spleen. In human reactive lymph node and tonsil, we identified spatially distinct TCR repertoires both between germinal center (GC) and non-GC regions as well as between GCs. We then spatially profiled T cell clonotypes and their infiltration in renal cell carcinoma specimens before and following immune checkpoint blockade, which identified uniquely distributed T cell clonotypes and transcriptional states, highlighting the infiltration and expression heterogeneity both between clonotypes and within a T cell clonotype. Our method is anticipated to facilitate dissection of the immune microenvironment, yielding insights into the complex spatial relationships between T cell clonotypes, neighboring cell types, and gene expression that drive T cell development and response to disease. This work was supported in part by the NIH U19AI082630, the Dana-Farber/Harvard Cancer Center Kidney Cancer SPORE (NCI P50CA101942), and the NCI IMAT grant.