Brentville Victoria A, Atabani Suha, Cook Katherine, Durrant Lindy G
Academic Department of Clinical Oncology, University of Nottingham, Nottingham, UK.
Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham, City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK.
Ther Adv Vaccines Immunother. 2018 Apr;6(2):31-47. doi: 10.1177/2515135518768769. Epub 2018 Apr 10.
The interplay between tumours and the immune system has long been known to involve complex interactions between tumour cells, immune cells and the tumour microenvironment. The progress of checkpoint inhibitors in the clinic in the last decade has highlighted again the role of the immune system in the fight against cancer. Numerous efforts have been undertaken to develop ways of stimulating the cellular immune response to eradicate tumours. These interventions include the identification of appropriate tumour antigens as targets for therapy. In this review, we summarize progress in selection of target tumour antigen. Targeting self antigens has the problem of thymic deletion of high-affinity T-cell responses leaving a diminished repertoire of low-affinity T cells that fail to kill tumour cells. Thymic regulation appears to be less stringent for differentiation of cancer-testis antigens, as many tumour rejection antigens fall into this category. More recently, targeting neo-epitopes or post-translational modifications such as a phosphorylation or stress-induced citrullination has shown great promise in preclinical studies. Of particular interest is that the responses can be mediated by both CD4 and CD8 T cells. Previous vaccines have targeted CD8 T-cell responses but more recently, the central role of CD4 T cells in orchestrating inflammation within tumours and also differentiating into potent killer cells has been recognized. The design of vaccines to induce such immune responses is discussed herein. Liposomally encoded ribonucleic acid (RNA), targeted deoxyribonucleic acid (DNA) or long peptides linked to toll-like receptor (TLR) adjuvants are the most promising new vaccine approaches. These exciting new approaches suggest that the 'Holy Grail' of a simple nontoxic cancer vaccine may be on the horizon. A major hurdle in tumour therapy is also to overcome the suppressive tumour environment. We address current progress in combination therapies and suggest that these are likely to show the most promise for the future.
长期以来，人们已知肿瘤与免疫系统之间的相互作用涉及肿瘤细胞、免疫细胞和肿瘤微环境之间的复杂相互作用。过去十年中，检查点抑制剂在临床上的进展再次凸显了免疫系统在抗癌斗争中的作用。人们已经做出了许多努力来开发刺激细胞免疫反应以根除肿瘤的方法。这些干预措施包括确定合适的肿瘤抗原作为治疗靶点。在本综述中，我们总结了在选择靶肿瘤抗原方面的进展。靶向自身抗原存在高亲和力T细胞反应在胸腺中被清除的问题，导致低亲和力T细胞库减少，而这些低亲和力T细胞无法杀死肿瘤细胞。胸腺调节对于癌睾丸抗原的分化似乎不那么严格，因为许多肿瘤排斥抗原都属于这一类别。最近，靶向新抗原表位或翻译后修饰（如磷酸化或应激诱导的瓜氨酸化）在临床前研究中显示出巨大的前景。特别令人感兴趣的是，这种反应可以由CD4和CD8 T细胞介导。以前的疫苗靶向CD8 T细胞反应，但最近，人们已经认识到CD4 T细胞在协调肿瘤内炎症以及分化为强效杀伤细胞方面的核心作用。本文讨论了诱导此类免疫反应的疫苗设计。脂质体编码的核糖核酸（RNA）、靶向脱氧核糖核酸（DNA）或与Toll样受体（TLR）佐剂连接的长肽是最有前途的新型疫苗方法。这些令人兴奋的新方法表明，一种简单无毒的癌症疫苗的“圣杯”可能即将出现。肿瘤治疗中的一个主要障碍也是克服抑制性肿瘤环境。我们阐述了联合治疗的当前进展，并表明这些联合治疗可能在未来显示出最大的前景。
