Defining the genetic determinants of CD8+ T cell receptor repertoire in the context of immune checkpoint blockade

The relationship between genetic variation and CD8⁺ T cell receptor (TCR) repertoire usage in patients receiving immune checkpoint blockade (ICB) therapy for cancer is unexplored. We have conducted a genome-wide and human leukocyte antigen (HLA)–focused analysis of CD8⁺ TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K-nucleotide oligomer usage from samples taken before and after ICB (n = 250). We identify 11 cis and 10 trans V-gene associations, primarily to the MHC, that meet genome-wide significance. TCR clones containing HLA associated V-genes were less stable across treatment, while, at the single-cell level, genetically associated clones demonstrate subset enrichment and increased tumor reactivity expression profiles. Notably, patients with HLA-matched TCR clones demonstrate improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of ICB treatment, with implications for understanding factors relating to therapeutic response and patient outcomes.