Molecular reconstruction of tumor-reactive γδ T-cell receptors using single-cell sequencing

Many human tumors escape immune attack through mechanisms that lower their neoantigen presentation by HLA-class-1, making themselves unidentifiable by CD8+ αβ T-cells. These tumors are typically harder to treat, more resistant to therapy, and have poorer outcomes. In these contexts, nontraditional immune cells such as NK- cells, γδ T-cells, and CD4+ T-cells, that are not reliant on HLA-class-1 neoantigen presentation have been gaining interest as alternate avenues for therapy. Increasing recent evidence has implicated γδ T-cells as potential effectors and determinants of prognosis in solid tumors. Here, we perform the first comprehensive analysis of Vδ1 γδ T- cells during anti-tumor immune response by leveraging paired single-cell transcriptomics and T-cell receptor sequencing, finding novel evidence that Vδ1 γδ T-cells engage in adaptive immune responses against tumor cells and undergo clonal expansion of their TCR repertoires. Additionally, we pilot proof-of-concept models to functionally validate the tumor-reactivity of patient-specific Vδ1 γδ TCRs and identify potential binding partners of these TCRs.--Author's abstract