Mei Yihan, Liu Yu, Liu Wenbing, Chen Manling, Liu Xiaoyu, Wang Shangshang, Mou Junli, Xing Haiyan, Tang Kejing, Tian Zheng, Rao Qing, Wang Min, Gu Runxia, Qiu Shaowei, Wang Jianxiang
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS&PUMC), Tianjin, 300020, China.
Tianjin Institutes of Health Science, Tianjin, 301600, China.
Exp Hematol Oncol. 2024 Sep 6;13(1):92. doi: 10.1186/s40164-024-00560-0.
Besides chemotherapy and hematopoietic stem cell transplantation (HSCT), autologous T cells can also serve as a new treatment approach for AML patients. However, the features of tumor-reactive T cells and their distinctive markers still lack full description. To evaluate the characteristics of tumor-reactive T cells, we collected bone marrow (BM) T cells from newly diagnosed AML patients with RUNX1::RUNX1T1 as examples for paired single-cell RNA sequencing and single-cell V(D)J sequencing. Based on the STARTRAC-like algorithm, we defined bystander T cells and tumor-reactive T cells. Compared with bystander T cells, tumor-reactive T cells presented as senescent-like cytotoxic terminally differentiated T cells (Temra) with upregulated NK-related markers. Additionally, we found ADGRG1 could serve as the specific marker of CD8 T tumor-reactive T cell and validated it through the Runx1; Mx1-Cre mouse model. In chimeric antigen receptor (CAR)-T and target cell system, ADGRG1 was selectively upregulated upon antigen-TCR encounter. Moreover, ADGRG1CD8 T cells released a higher level of IFN-γ and showed higher cell-killing ability when exposed to matched AML blasts. Together, our findings depict the single-cell profile of tumor-reactive T cells in AML BM and propose that ADGRG1 can act as an indicator of T cell tumor reactivity in AML, which may be further harnessed for adoptive cell therapy and tumor-reactive TCR enrichment.
除了化疗和造血干细胞移植（HSCT）外，自体T细胞也可作为急性髓系白血病（AML）患者的一种新的治疗方法。然而，肿瘤反应性T细胞的特征及其独特标志物仍缺乏全面描述。为了评估肿瘤反应性T细胞的特征，我们收集了新诊断的以RUNX1::RUNX1T1为特征的AML患者的骨髓（BM）T细胞，作为配对单细胞RNA测序和单细胞V(D)J测序的样本。基于类似STARTRAC的算法，我们定义了旁观者T细胞和肿瘤反应性T细胞。与旁观者T细胞相比，肿瘤反应性T细胞表现为衰老样细胞毒性终末分化T细胞（Temra），其NK相关标志物上调。此外，我们发现ADGRG1可作为CD8 T肿瘤反应性T细胞的特异性标志物，并通过Runx1;Mx1-Cre小鼠模型进行了验证。在嵌合抗原受体（CAR）-T和靶细胞系统中，ADGRG1在抗原-TCR相遇时被选择性上调。此外，ADGRG1 CD8 T细胞在暴露于匹配的AML原始细胞时释放出更高水平的干扰素-γ，并表现出更高的细胞杀伤能力。总之，我们的研究结果描绘了AML骨髓中肿瘤反应性T细胞的单细胞图谱，并提出ADGRG1可作为AML中T细胞肿瘤反应性的指标，这可能进一步用于过继性细胞治疗和肿瘤反应性TCR富集。
