Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
Zhejiang University School of Medicine, Hangzhou, 310058, China.
Cancer Lett. 2023 Sep 1;571:216336. doi: 10.1016/j.canlet.2023.216336. Epub 2023 Aug 9.
The efficacy of HCC (hepatocellular carcinoma) immunotherapy is hindered by the limited reactivity and short duration of tumor-infiltrating T cells. These deficiencies may be ascribed to the proliferative ability of T cells. The primary objective of this study was to identify the key factor regulating tumor-infiltrating lymphocytes (TIL) proliferation within the HCC microenvironment. Through the utilization of tissue-infiltrated T cell proteomics and fraction proteomics, we analyzed the differential proteins in T cells among HCC, liver fibrosis, and hemangioma (serving as controls) groups. Additionally, we examined the differential regulatory TFs of T cells between the HCC and VH (volunteer healthy, as a control) groups. Using cyTOF and flow cytometry technologies, as well as generating CD8 T-specific BMI1 knockout mice, we confirmed that BMI1 controls CD127KLRG1 memory cell differentiation. Through RNA-seq and MeRIP-seq, we verified that BMI1 regulates TCF1 expression independently of its classical function. Furthermore, by conducting Tyramide signal amplification (TSA) IHC analysis, employing a hydrodynamic mouse HCC model, and utilizing liver-specific nanoparticle targeting therapy, we demonstrated that BMI1 in HCC influences the proliferation of infiltrating CD8+T. BMI1 inhibition promotes effector T cell differentiation while suppressing memory T cell differentiation. Moreover, liver-specific BMI1 knockdown proves beneficial in ameliorating T cell dysfunction and decelerating HCC progression. Our research group has pioneered the exploration of the proteomics of HCC-infiltrated T cells, shedding light on the pivotal role of BMI1 in controlling CD127+KLRG1+ memory CD8 T cell differentiation, which serves as the cornerstone for achieving immunotherapy efficacy in HCC.
肝癌（HCC）免疫疗法的疗效受到肿瘤浸润 T 细胞反应性和持续时间有限的阻碍。这些缺陷可能归因于 T 细胞的增殖能力。本研究的主要目的是确定调节 HCC 微环境中肿瘤浸润淋巴细胞（TIL）增殖的关键因素。通过利用组织浸润 T 细胞蛋白质组学和部分蛋白质组学，我们分析了 HCC、肝纤维化和血管瘤（作为对照）组 T 细胞中的差异蛋白。此外，我们还检查了 HCC 和 VH（志愿者健康，作为对照）组之间 T 细胞差异调节 TFs。使用 cyTOF 和流式细胞术技术，以及生成 CD8 T 特异性 BMI1 敲除小鼠，我们证实 BMI1 控制 CD127+KLRG1 记忆细胞分化。通过 RNA-seq 和 MeRIP-seq，我们验证了 BMI1 独立于其经典功能调节 TCF1 的表达。此外，通过进行酪胺信号放大（TSA）免疫组化分析、使用水力驱动的小鼠 HCC 模型以及利用肝脏特异性纳米颗粒靶向治疗，我们表明 HCC 中的 BMI1 影响浸润性 CD8+T 的增殖。BMI1 抑制促进效应 T 细胞分化，同时抑制记忆 T 细胞分化。此外，肝脏特异性 BMI1 敲低有助于改善 T 细胞功能障碍并减缓 HCC 进展。我们的研究小组率先探索了 HCC 浸润 T 细胞的蛋白质组学，揭示了 BMI1 在控制 CD127+KLRG1+记忆 CD8 T 细胞分化中的关键作用，这是实现 HCC 免疫疗法疗效的基石。
