Knutson K L, Disis M L
Department of Immunology, Mayo Clinic College of Medicine, 342C Guggenheim Bldg., 200 First St. SW, Rochester, MN 55906, USA.
Cancer Immunol Immunother. 2005 Aug;54(8):721-8. doi: 10.1007/s00262-004-0653-2. Epub 2005 Jan 27.
Historically, cancer-directed immune-based therapies have focused on eliciting a cytotoxic T cell (CTL) response, primarily due to the fact that CTL can directly kill tumors. In addition, many putative tumor antigens are intracellular proteins, and CTL respond to peptides presented in the context of MHC class I which are most often derived from intracellular proteins. Recently, increasing importance is being given to the stimulation of a CD4+ T helper cell (Th) response in cancer immunotherapy. Th cells are central to the development of an immune response by activating antigen-specific effector cells and recruiting cells of the innate immune system such as macrophages and mast cells. Two predominant Th cell subtypes exist, Th1 and Th2. Th1 cells, characterized by secretion of IFN-gamma and TNF-alpha, are primarily responsible for activating and regulating the development and persistence of CTL. In addition, Th1 cells activate antigen-presenting cells (APC) and induce limited production of the type of antibodies that can enhance the uptake of infected cells or tumor cells into APC. Th2 cells favor a predominantly humoral response. Particularly important during Th differentiation is the cytokine environment at the site of antigen deposition or in the local lymph node. Th1 commitment relies on the local production of IL-12, and Th2 development is promoted by IL-4 in the absence of IL-12. Specifically modulating the Th1 cell response against a tumor antigen may lead to effective immune-based therapies. Th1 cells are already widely implicated in the tissue-specific destruction that occurs during the pathogenesis of autoimmune diseases, such as diabetes mellitus and multiple sclerosis. Th1 cells directly kill tumor cells via release of cytokines that activate death receptors on the tumor cell surface. We now know that cross-priming of the tumor-specific response by potent APC is a major mechanism of the developing endogenous immune response; therefore, even intracellular proteins can be presented in the context of MHC class II. Indeed, recent studies demonstrate the importance of cross-priming in eliciting CTL. Many vaccine strategies aim to stimulate the Th response specific for a tumor antigen. Early clinical trials have shown that focus on the Th effector arm of the immune system can result in significant levels of both antigen-specific Th cells and CTL, the generation of long lasting immunity, and a Th1 phenotype resulting in the development of epitope spreading.
从历史上看，以癌症为导向的免疫疗法主要致力于引发细胞毒性T细胞（CTL）反应，这主要是因为CTL能够直接杀死肿瘤细胞。此外，许多假定的肿瘤抗原是细胞内蛋白，而CTL会对主要源自细胞内蛋白的MHC I类分子提呈的肽段产生反应。最近，在癌症免疫治疗中，刺激CD4 + T辅助细胞（Th）反应的重要性日益凸显。Th细胞通过激活抗原特异性效应细胞并募集天然免疫系统的细胞（如巨噬细胞和肥大细胞），在免疫反应的发展中起着核心作用。主要存在两种Th细胞亚型，即Th1和Th2。以分泌γ干扰素和肿瘤坏死因子-α为特征的Th1细胞，主要负责激活和调节CTL的发育及持久性。此外，Th1细胞激活抗原呈递细胞（APC），并诱导产生有限数量的特定类型抗体，这些抗体可增强感染细胞或肿瘤细胞被APC摄取。Th2细胞则主要引发体液免疫反应。在Th细胞分化过程中，抗原沉积部位或局部淋巴结处的细胞因子环境尤为重要。Th1细胞的分化依赖于局部产生的白细胞介素-12，而在没有白细胞介素-12的情况下，白细胞介素-4会促进Th2细胞的发育。特异性调节针对肿瘤抗原的Th1细胞反应可能会带来有效的免疫疗法。Th1细胞已被广泛认为与自身免疫性疾病（如糖尿病和多发性硬化症）发病过程中发生的组织特异性破坏有关。Th1细胞通过释放激活肿瘤细胞表面死亡受体的细胞因子直接杀死肿瘤细胞。我们现在知道，强效APC对肿瘤特异性反应的交叉提呈是内源性免疫反应发展的主要机制；因此，即使是细胞内蛋白也可以在MHC II类分子的背景下被提呈。事实上，最近的研究证明了交叉提呈在引发CTL中的重要性。许多疫苗策略旨在刺激针对肿瘤抗原的Th反应。早期临床试验表明，关注免疫系统的Th效应臂可导致产生大量的抗原特异性Th细胞和CTL，产生持久免疫力，并形成导致表位扩展的Th1表型。
