文章：

调节T细胞对肿瘤的免疫：监测T细胞反应的新策略

Modulating T-cell immunity to tumours: new strategies for monitoring T-cell responses

原文发布日期：2002-06-01

DOI: 10.1038/nrc820

类型: Review Article

开放获取: 否

要点：

1. The identification of many human tumour antigens as potential targets for immunotherapy has led to clinical trials to augment the tumour immune response through the use of vaccines and adoptively transferred T cells. Immunological monitoring in these studies will be crucial for understanding the principles that underlie successful immunotherapeutic strategies.
2. Recent advances in immunological monitoring now enable more-direct detection of individual antigen-specific T cells on the basis of structural or functional properties. These advanced assays provide a degree of specificity and sensitivity that was not previously possible with classical cytolytic or proliferation assays.
3. Structure-based assays — through the use of peptide–MHC (major histocompatibility complex) multimers that bind antigen-specific T-cell receptors (TCRs), or quantitative polymerase chain reaction (PCR) assays that detect clone-specific regions of the TCR — provide an estimation of the total number of T cells independent of functional status. Such tests are highly sensitive but can be difficult to implement in large-scale studies.
4. Function-based assays — such as ELISPOT analysis, which detects antigen-specific T cells on the basis of proximal cytokine production — provide a reliable measure of the reactive T-cell population and are amenable to high-throughput analysis. However, ELISPOT analysis and other function-based assays — intracellular cytokine analysis, quantitative real-time PCR analysis of cytokine expression — might underestimate or fail to detect naive, anergic or functionally unresponsive antigen-specific T cells.
5. Judicious use of these advanced assays to monitor the immune response in clinical trials can be used to address questions related to the magnitude, homing property, function and avidity of anti-tumour T cells that are required for effective therapy.
6. An important corollary to an evaluation of the T-cell response will be an understanding of the tumour response to immune manipulation, particularly an evaluation of potential mechanisms of immune escape.
7. Pre-clinical and clinical studies have shown that tumour cells might circumvent the immune response through defective antigen expression and presentation, inhibition of T-cell effector function and induction of anti-apoptotic mechanisms.
8. Occasional application of immunological assays to current clinical trials has not always shown a correlation between increased immune response and clinical response. It is anticipated that incorporation of these advanced assays into future trials of antigen-specific immunotherapy, accompanied by evaluation for mechanisms of tumour immune escape, will help to explain these discrepancies and elucidate requirements for more-effective therapy.

要点翻译：

1. 许多人类肿瘤抗原被确定为免疫治疗的潜在靶点，这促使我们通过疫苗和过继性T细胞移植来增强肿瘤免疫反应的临床试验。这些研究中的免疫监测对于理解成功免疫治疗策略的基本原则至关重要。
2. 免疫监测技术的最新进展使得能够基于结构或功能特性更直接地检测个体抗原特异性T细胞。这些先进检测方法提供的特异性和灵敏度是传统细胞溶解或增殖测定无法实现的。
3. 基于结构的检测——通过使用肽段-MHC（主要组织相容性复合体）多聚体结合抗原特异性T细胞受体（TCR），或采用定量聚合酶链反应（PCR）检测TCR克隆特异性区域——可估算不依赖功能状态的总T细胞数量。此类检测具有高灵敏度，但在大规模研究中实施可能较为困难。
4. 基于功能的检测——如ELISPOT分析（通过检测近期细胞因子产生来识别抗原特异性T细胞）——能可靠测量反应性T细胞群，并适用于高通量分析。然而ELISPOT分析及其他功能检测（包括细胞内细胞因子分析、细胞因子表达的实时定量PCR分析）可能会低估或无法检测初始型、无反应性或功能失活的抗原特异性T细胞。
5. 在临床试验中合理运用这些先进检测方法进行免疫监测，有助于探究有效治疗所需抗肿瘤T细胞的数量、归巢特性、功能及亲和力等关键问题。
6. 评估T细胞反应的重要推论将是理解肿瘤对免疫操纵的反应，特别是评估潜在的免疫逃逸机制。
7. 临床前和临床研究表明，肿瘤细胞可能通过缺陷性抗原表达与呈递、抑制T细胞效应功能以及诱导抗凋亡机制来规避免疫反应。
8. 在当前临床试验中偶尔应用的免疫检测并不总是显示免疫反应增强与临床反应之间的相关性。预计将这些先进检测方法纳入未来抗原特异性免疫治疗试验，并同步评估肿瘤免疫逃逸机制，将有助于解释这些差异并阐明更有效治疗的要求。

英文摘要：

Advances in immunological monitoring provide the means to analyse the cellular immune response with greater sensitivity and precision than ever before. Novel immunological tools can be used not only to quantify the antigen-specific response, but also to analyse the phenotype and function of individual effector cells. Application of these tools to dissect the antitumour responses will lead to a greater understanding of the principles that underlie successful immunotherapeutic strategies and potential mechanisms of tumour immune evasion.

摘要翻译： 

免疫监测技术的进步使我们能够以前所未有的敏感性和精确度分析细胞免疫应答。新型免疫学工具不仅可用于定量抗原特异性应答，还可用于分析单个效应细胞的表型和功能。应用这些工具来剖析抗肿瘤应答，将有助于更深入地理解成功免疫治疗策略背后的原理，以及肿瘤免疫逃逸的潜在机制。

原文链接：

Modulating T-cell immunity to tumours: new strategies for monitoring T-cell responses