Dynamics of The Γδtcr Repertoires During The Dedifferentiation Process and Pilot Implications for Immunotherapy of Thyroid Cancer

Abstract γδ T cells are evolutionarily conserved T lymphocytes that manifest unique antitumor efficacy independent of tumor mutation burden (TMB) and conventional human leukocyte antigen (HLA) recognition. However, the dynamic changes in their T cell receptor (TCR) repertoire during cancer progression and treatment courses remain unclear. Here, a comprehensive characterization of γδTCR repertoires are performed in thyroid cancers with divergent differentiation states through cross‐sectional studies. The findings revealed a significant correlation between the differentiation states and TCR repertoire diversity. Notably, highly expanded clones are prominently enriched in γδ T cell compartment of dedifferentiated patients. Moreover, by longitudinal investigations of the γδ T cell response to various antitumor therapies, it is found that the emergence and expansion of the Vδ2neg subset may be potentially associated with favorable clinical outcomes after post‐radiotherapeutic immunotherapy. These findings are further validated at single‐cell resolution in both advanced thyroid cancer patients and a murine model, underlining the importance of further investigations into the role of γδTCR in cancer immunity and therapeutic strategies.