Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, India.
Cancer Lett. 2023 Jun 28;564:216194. doi: 10.1016/j.canlet.2023.216194. Epub 2023 Apr 20.
Metastatic Renal Cell Carcinoma (mRCC) remains incurable, despite the current checkpoint-blockade-driven, limited overall response rate. The CD8 memory T cells can mount a rapid and an effective response. The ubiquitin ligase RAD6-KCMF1-UBR4-mediated regulation of autophagy in CD8 memory T cells in patients with renal cell carcinoma (RCC) remains unexplored. Consequently, flow cytometry was used to study memory T cells, and their subsets, including activation and regulatory phenotypes in peripheral blood mononuclear cells (PBMCs). Expression of the ubiquitin ligase and autophagy was measured both at the cellular and molecular levels in memory T cells of patients with RCC. JC.1 staining and Annexin/PI assays were used to evaluate the memory T cells depolarization and apoptosis rates. The results indicated that the disruption of Ub-E2-E3 complex and impaired autophagy in memory T cells diminished their ability to survive and combat against tumor cells. Inhibition of memory T cells apoptosis by targeting E3 ubiquitin ligase or autophagy pathways can be explored as a potential therapeutic strategy to improve the long-term survival of memory T cells in RCC.
转移性肾细胞癌（mRCC）仍然无法治愈，尽管目前的检查点阻断驱动，整体反应率有限。CD8 记忆 T 细胞可以迅速有效地做出反应。RAD6-KCMF1-UBR4 介导的泛素连接酶在肾细胞癌（RCC）患者 CD8 记忆 T 细胞中的自噬调节尚未被探索。因此，使用流式细胞术研究了外周血单个核细胞（PBMC）中的记忆 T 细胞及其亚群，包括激活和调节表型。在 RCC 患者的记忆 T 细胞中，在细胞和分子水平上均测量了泛素连接酶和自噬的表达。使用 JC.1 染色和 Annexin/PI 测定来评估记忆 T 细胞去极化和凋亡率。结果表明，Ub-E2-E3 复合物的破坏和记忆 T 细胞中自噬的受损削弱了它们对抗肿瘤细胞的存活和攻击能力。通过靶向 E3 泛素连接酶或自噬途径抑制记忆 T 细胞凋亡，可以作为提高 RCC 中记忆 T 细胞长期存活的潜在治疗策略进行探索。
