Dynamics of ?d TCR repertoire during the de-differentiation and treatment course of thyroid cancer [mouse scRNA]

Although the de-differentiation process of thyroid cancer has been studied, it remains unclear how T cell antigen receptor (TCR) dynamically changes during the cancer progression and treatment. Here we characterized the ?d TCR repertoire along the de-differentiation of thyroid cancers cross-sectionally and investigated the longitudinal changes of TCR components over time in thyroid cancer patients receiving different treatment. We found that better differentiated status was significantly related to greater diversity and lower clonality. Expanded TCRs show enhanced convergent recombination and improved antigen-driven anti-tumor immune responses. The longitudinal study suggested that post-radiotherapeutic immunotherapy led to favorable clinical outcome, which was attributed to the appearance and expansion of neo clonotypes and was validated by scRNA-seq data and murine model experiment. These findings provided a novel understanding in the progression of thyroid cancer and highlighted the role of ?d T cells in anti-tumor immunity. Overall design: 8-week-old TBP (Tpo-Cre, Braftm1Mmcm/wz TrP53tm1Brn/tm1Brn) mice were induced by i.p. administration of 150 mg/kg tamoxifen dissolved in corn oil for two times. 40 days after induction, mice were randomized into 4 groups: the control group, radiotherapy group, immunotherapy group and combined treatment group (5 mice/group). Control group was intraperitoneally injected with Isotype antibody (5mg/kg, q.3d for 8 weeks), the radiotherapy group was received sublethal irradiated (2.5Gy, q.3d for 3 times) the immunotherapy group was intraperitoneally injected with anti-PD-1 antibody (BioXCell) (5mg/kg, q.3d for 8 weeks), and the combined treatment group received both sublethal irradiated (2.5Gy, q.3d for 3 times) and anti-PD-1 antibody (Bxcell) (5mg/kg, q.3d for 8 weeks). The mice were sacrificed after 8 weeks of treatment or euthanized due to respiratory distress caused by tumor compression or obvious body weight lost (> 20%).