Emily Jackson and colleagues have identified 11 families of T cell receptors shared across multiple cancer patients, including nine previously unknown families, by analyzing genetic data from more than 150,000 tumor samples, according to a study published in Science Translational Medicine, News-Medical reported.
The team constructed a database comprising bulk RNA sequencing data, clinical records, and T cell receptor chains from patients with more than 30 types of advanced cancer. They developed an analytical pipeline to examine 26 million unique T cell receptor chains, uncovering receptors associated with common cancer antigens such as mutated KRAS protein and human papillomavirus proteins.
“More broadly, our findings demonstrate that patient-derived immune repertoires captured during routine clinical testing represent a valuable and largely untapped resource for cancer immunotherapy discovery,” Jackson and colleagues concluded in the study.
How T Cell Receptors Recognize Cancer
T cells carry T cell receptors in their cell membranes that bind specific antigens, and because these receptors can target tumor cells specifically, they offer a route for anticancer therapies, according to a review published in PubMed Central. A functional receptor is a heterodimer composed of two paired protein chains, formed either by alpha and beta chains or by gamma and delta chains. Most T cells express alpha-beta T cell receptors that recognize antigens presented on major histocompatibility complex proteins, while only 1% to 5% express gamma-delta receptors, which are not restricted by major histocompatibility complex proteins and participate in innate immune responses; for these reasons, alpha-beta receptors are typically the focus of T cell receptor sequencing and clinical applications. T cells become antigen-experienced after encountering their cognate antigen presented on major histocompatibility complex molecules through these receptors.
Each receptor’s variable region assembles through V(D)J recombination, a process in which gene segments randomly combine to create a unique antigen-binding site, the review explains. In this ordered process, a diversity segment first recombines with a joining segment, and the resulting combination then joins with a variable segment before linking to the constant region to form a functioning chain; the CDR3 region of the beta chain sits within the antigen-binding site. This diversity makes T cell receptors difficult to discover using current techniques, which require labor-intensive workflows and tissue specimens that are difficult to acquire.
Why Public Receptors Matter for Therapy
Current methods for discovering new T cell receptors demand labor-intensive laboratory work and hard-to-obtain tissue samples, but the new pipeline uses public datasets from large patient cohorts instead. By finding “public” receptors shared across patients, the approach could accelerate efforts to use these receptors in immunotherapies against multiple cancer types, News-Medical reported.
Questions About the Discovery
More than 150,000 patients with over 30 different types of advanced cancer.
The receptors were associated with mutated KRAS protein and human papillomavirus proteins.
According to the PubMed Central review, scientists do not yet know which exact ligands gamma-delta T cells bind.
The study appears in Science Translational Medicine in 2026 under DOI 10.1126/scitranslmed.aeh8192.