γδ T-cell Receptors Derived from Breast Cancer-Infiltrating T Lymphocytes Mediate Antitumor Reactivity

Area of Science:

• Immunology
• Oncology

Background:

• Gamma delta (γδ) T cells within human solid tumors are not well understood.
• Their role in breast cancer, specifically, requires further definition.

Purpose of the Study:

• To analyze the molecular and functional characteristics of T-cell receptors (TCRs) from tumor-infiltrating γδ T lymphocytes (γδ TILs) in breast cancer.
• To investigate the potential of these γδ TILs and their TCRs in mediating antitumor responses.

Main Methods:

• Analysis of T-cell receptors (TCRs) from archival breast cancer lesions.
• Molecular and functional characterization of tumor-infiltrating γδ T lymphocytes (γδ TILs).
• Reconstruction of matched Vδ2 TCRγ and TCRδ pairs using single-cell sequencing.

Main Results:

• The majority of γδ TILs exhibited a proinflammatory phenotype, with a minority expressing IL17.
• A higher proportion of Vδ2+ T cells was observed in breast cancer compared to other tumor types.
• γδ TIL-derived TCRs demonstrated reactivity against tumor cells, dependent on both TCRγ and TCRδ chains, independent of other innate immune receptors.

Conclusions:

• γδ TILs can mediate tumor reactivity through their unique γδ TCR pairs.
• Engineered T cells expressing γδ TIL-derived TCRs show potent antitumor reactivity against various cancer types.
• These findings suggest γδ TILs are a valuable resource for developing adoptive cell therapies.