Okoye Isobel S, Houghton Michael, Tyrrell Lorne, Barakat Khaled, Elahi Shokrollah
Department of Dentistry, University of Alberta, Edmonton, AB, Canada.
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
Front Immunol. 2017 Sep 29;8:1215. doi: 10.3389/fimmu.2017.01215. eCollection 2017.
In cancer and chronic viral infections, T cells are exposed to persistent antigen stimulation. This results in expression of multiple inhibitory receptors also called "immune checkpoints" by T cells. Although these inhibitory receptors under normal conditions maintain self-tolerance and prevent immunopathology, their sustained expression deteriorates T cell function: a phenomenon called exhaustion. Recent advances in cancer immunotherapy involve blockade of cytotoxic T lymphocyte antigen-4 and programmed cell death 1 in order to reverse T cell exhaustion and reinvigorate immunity, which has translated to dramatic clinical remission in many cases of metastatic melanoma and lung cancer. With the paucity of therapeutic vaccines against chronic infections such as HIV, HPV, hepatitis B, and hepatitis C, such adjunct checkpoint blockade strategies are required including the blockade of other inhibitory receptors such as T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domains, T cell Ig and mucin-domain containing-3, lymphocyte activation gene 3, and V-domain Ig-containing suppressor of T cell activation. The nature of different chronic viral infections and cancers is likely to influence the level, composition, and pattern of inhibitory receptors expressed by responding T cells. This will have implications for checkpoint antibody blockade strategies employed for treating tumors and chronic viral infections. Here, we review recent advances that provide a clearer insight into the role of coinhibitory receptor expression in T cell exhaustion and reveal novel antibody-blockade therapeutic targets for chronic viral infections and cancer. Understanding the mechanism of T cell exhaustion in response to chronic virus infections and cancer as well as the nature of restored T cell responses will contribute to further improvement of immune checkpoint blockade strategies.
在癌症和慢性病毒感染中，T细胞会受到持续的抗原刺激。这导致T细胞表达多种抑制性受体，也被称为“免疫检查点”。尽管这些抑制性受体在正常情况下维持自身耐受性并防止免疫病理，但它们的持续表达会使T细胞功能恶化：这种现象被称为耗竭。癌症免疫疗法的最新进展包括阻断细胞毒性T淋巴细胞抗原4和程序性细胞死亡蛋白1，以逆转T细胞耗竭并恢复免疫活力，这在许多转移性黑色素瘤和肺癌病例中已转化为显著的临床缓解。由于针对HIV、HPV、乙型肝炎和丙型肝炎等慢性感染的治疗性疫苗匮乏，需要采用此类辅助性检查点阻断策略，包括阻断其他抑制性受体，如含有免疫球蛋白（Ig）和基于免疫受体酪氨酸的抑制基序结构域的T细胞免疫受体、T细胞免疫球蛋白和粘蛋白结构域包含3、淋巴细胞活化基因3以及含V结构域Ig的T细胞活化抑制因子。不同慢性病毒感染和癌症的性质可能会影响反应性T细胞表达的抑制性受体的水平、组成和模式。这将对用于治疗肿瘤和慢性病毒感染的检查点抗体阻断策略产生影响。在此，我们综述了近期的进展，这些进展为共抑制性受体表达在T细胞耗竭中的作用提供了更清晰的认识，并揭示了针对慢性病毒感染和癌症的新型抗体阻断治疗靶点。了解T细胞对慢性病毒感染和癌症产生耗竭的机制以及恢复的T细胞反应的性质，将有助于进一步改进免疫检查点阻断策略。
