Starved and Asphyxiated: How Can CD8(+) T Cells within a Tumor Microenvironment Prevent Tumor Progression.
Starved and Asphyxiated: How Can CD8(+) T Cells within a Tumor Microenvironment Prevent Tumor Progression.
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DOI：
10.3389/fimmu.2016.00032
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发表时间：
2016
影响因子：
7.3
通讯作者：
Ertl HC
中科院分区：
文献类型：
--
作者：
Zhang Y;Ertl HC
尽管近年来癌症免疫治疗取得了重大突破，但其总体疗效在大多数患者中仍然有限。一个主要障碍是肿瘤抗原特异性CD 8+肿瘤浸润淋巴细胞（TIL）的耗竭，这通常归因于肿瘤微环境（TME）内抗原的持续刺激。最近的一系列研究表明，TME对TIL构成了重大的代谢挑战，这可能导致其功能衰竭。缺氧增加活化的CD 8 + T细胞上的共抑制剂的表达，这通常降低T细胞的效应子功能。它还损害细胞通过氧化磷酸化获得能量的能力。葡萄糖限制增加程序性细胞死亡蛋白-1的表达并降低活化的CD 8 + T细胞的功能。缺氧和低血糖的组合，如在实体瘤中常见的，通过影响能量产生的两个主要途径，将CD 8 + TIL置于双重代谢危险中。最近，许多研究涉及代谢应激对调节CD 8 + T细胞代谢、分化和功能的影响。在这里，我们讨论了TME内不同类型的代谢应激如何塑造CD 8 + T细胞的肿瘤杀伤能力的最新研究结果。我们提出，操纵TIL的代谢以更有效地利用营养物质，特别是在间歇性缺氧期间，可以最大限度地提高它们的性能，延长它们的生存期，并提高主动癌症免疫治疗的疗效。
Although cancer immunotherapy has achieved significant breakthroughs in recent years, its overall efficacy remains limited in the majority of patients. One major barrier is exhaustion of tumor antigen-specific CD8+ tumor-infiltrating lymphocytes (TILs), which conventionally has been attributed to persistent stimulation with antigen within the tumor microenvironment (TME). A series of recent studies have highlighted that the TME poses significant metabolic challenges to TILs, which may contribute to their functional exhaustion. Hypoxia increases the expression of coinhibitors on activated CD8+ T cells, which in general reduces the T cells’ effector functions. It also impairs the cells’ ability to gain energy through oxidative phosphorylation. Glucose limitation increases the expression of programed cell death protein-1 and reduces functions of activated CD8+ T cells. A combination of hypoxia and hypoglycemia, as is common in solid tumors, places CD8+ TILs at dual metabolic jeopardy by affecting both major pathways of energy production. Recently, a number of studies addressed the effects of metabolic stress on modulating CD8+ T cell metabolism, differentiation, and functions. Here, we discuss recent findings on how different types of metabolic stress within the TME shape the tumor-killing capacity of CD8+ T cells. We propose that manipulating the metabolism of TILs to more efficiently utilize nutrients, especially during intermittent periods of hypoxia could maximize their performance, prolong their survival and improve the efficacy of active cancer immunotherapy.