Characterization of Tumor-Infiltrating T-Cell Repertoire in Human Cancers

SITC Annual Meeting 2021 Presentation
Authors Taylor Harding, Qidi Yang, Brittany Mineo, Jenna Malinauskas, Jason Perera, Karl Beutner, Denise Lau, and Aly Khan

Background TCR and BCR repertoire profiling is a promising technique that can provide a clinically useful window into the complex interactions between tumor cells and infiltrating lymphocytes. Despite recent advances in repertoire sequencing methods, the characterization of tumor-infiltrating T-cell repertoires has been limited to small sample sizes due to technical and material constraints. In this study, we constructed a large multidimensional database of repertoire data covering a diverse landscape of HLA genotypes and tumor neoantigens from routine clinical sequencing. We present a descriptive summary of repertoire profiles derived from tens of thousands of tumor samples from over fifty different cancer cohorts and characterize the associations between T-cell repertoires and various clinical and molecular features.

Methods To enrich immune receptor transcripts detected by the Tempus RNA-sequencing workflow, hybrid capture probes tiling TCR and BCR genes were used. Repertoire profiling reads were aligned, assembled, and annotated against IMGT reference sequences. Repertoires are profiled as a component of Tempus|xT RNA sequencing and are summarized here for >25 thousand tumor samples from over 50 different cancer cohorts.

Results We demonstrate that the use of TCR/BCR hybrid capture probes is an effective method for enriching immune receptor transcripts in RNA-sequencing data without interfering with downstream transcriptomic analysis. These repertoires were profiled as part of a larger, multimodal DNA/RNA-sequencing pipeline that quantifies a variety of tumor clinical and molecular features. We explored the correlation between high-level repertoire metrics like richness (the number of unique receptor clonotypes in a given repertoire) and clonality/evenness (Shannon entropy) against both gene expression-based metrics (i.e. immune cell infiltration estimates, etc.) and mutational patterns (mutational burden and neoantigen load). Finally, we observed that the repertoire clonality of B-cell and T-cell driven cancers frequently exhibits clear monoclonal dominance for the tumor cells’ lymphoid receptors.

Conclusions TCR/BCR repertoire profiling can be incorporated into high-volume clinical RNA sequencing to generate a diverse multimodal dataset for studying the tumor-immune microenvironment. By creating a large-scale database of TCR/BCR repertoire profiles from a variety of tissue, HLA genotypes, and mutational contexts, we can better resolve the molecular and clinical correlates of cancer with host adaptive immunity.