Sophia Liu

Conference 2023 Live Talk

Talk title

Spatial maps of T cell receptors and transcriptomes reveal distinct immune niches and interactions in the adaptive immune response

Authors and Affiliations

Sophia Liu1,2,3,13, J. Bryan Iorgulescu3,4,5,13, Shuqiang Li3,4,6,13, Mehdi Borji3,4, Irving A. Barrera-Lopez3, Vignesh Shanmugam3,5, Haoxiang Lyu4,6, Julia W. Morriss3, Zoe N. Garcia3,7, Evan Murray3, David A. Reardon4,8, Charles H. Yoon9, David A. Braun3,4,8,10, Kenneth J. Livak4,6, Catherine J. Wu3,4,8,11,14, Fei Chen3,12,14

1. Biophysics Program, Harvard University, Boston, MA 02115, USA
2. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
3. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
5. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
6. Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA 02215, USA
7. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
8. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
9. Department of Surgical Oncology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
10. Yale Center of Cellular and Molecular Oncology, Yale School of Medicine, New Haven, CT 06511
11. Division of Stem Cell Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Boston, MA 02215, USA
12. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
13. These authors contributed equally
14. Senior authors

Abstract

Background

In many diseases, antigen-specific T cells function as the primary effector cells that mediate immune responses. T cells mediate antigen-specific immune responses to disease through the specificity and diversity of their T-cell receptors (TCRs). Conventional single-cell and bulk sequencing approaches lose valuable information about where T cells are. Determining the spatial distributions of T cell clonotypes in tissues is essential to understand T cell maturation and behavior, but spatial sequencing methods remain unable to profile the TCR repertoire.

Methods

Here, we develop Slide-TCR-seq, a spatial method to sequence whole transcriptomes and TCRs within intact tissues. Slide-TCR-seq uses DNA-barcoded 10-µm beads affixed to slides, in situ sequenced, and used to capture RNA for downstream library preparation. We then take the cDNA and perform a targeted amplification of the TCR sequencing for subsequent short or long-read sequencing to identify the variable region.

Results

We confirm the ability of Slide-TCR-seq to map the characteristic architecture of T cells and their receptors in the mouse spleen. We identified spatially distinct TCR repertoires in human lymph nodes and tonsil. Spatial profiling of T cell clonotypes and their infiltration in renal cell carcinoma and melanoma specimens identified inter- and intra-clonotype transcriptional spatial and gene expression heterogeneity. We found that some clones exhibited significantly higher tumor infiltration than others, and some clones showed poorly infiltrated T cells expressing higher levels of a geneset predicting poor response to immunotherapy. Furthermore, we identify cell-cell interactions between a TCR clone and adjacent tumor cells unique to that clone, highlighting the potential to study clonal cell-cell interactions. Last, we can also identify polyadenylated viral transcripts in the spatial context.

Conclusions

Our method facilitates the dissection of the immune microenvironment across disease and developmental contexts, yielding insights into the complex spatial relationships between T cell clonotypes, neighboring cell types, and gene expression that drive T cell responses.