Gajewski Thomas F
Departments of Pathology and Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5256-61. doi: 10.1158/1078-0432.CCR-07-0892.
The clinical investigation of numerous therapeutic cancer vaccine strategies has resulted in relative disappointment. Whereas a minority of patients have indeed experienced clinical benefit, the majority of patients show disease progression even in cases in which induction of functional tumor antigen-specific T-cell responses as measured in the blood is easily detected. This observation has led to interrogation of the tumor microenvironment for potential mechanisms of tumor resistance to the effector phase of the antitumor T-cell response. Poor chemokine-mediated trafficking of effector cells and the action of negative regulatory pathways that inhibit T-cell function have been identified as key limiting factors. Important negative regulatory pathways include T-cell anergy from insufficient B7 costimulation, extrinsic suppression by regulatory T-cell populations, direct inhibition through inhibitory ligands such as PD-L1, and metabolic dysregulation such as through the activity of indoleamine 2,3-dioxygenase. Recognition of these evasion mechanisms has pointed toward new therapeutic approaches for cancer immunotherapy.
众多治疗性癌症疫苗策略的临床研究结果相对令人失望。虽然少数患者确实获得了临床益处，但大多数患者即便在血液中能轻易检测到功能性肿瘤抗原特异性T细胞反应诱导的情况下，仍出现疾病进展。这一观察结果促使人们对肿瘤微环境进行研究，以探寻肿瘤对抗肿瘤T细胞反应效应阶段产生抗性的潜在机制。趋化因子介导的效应细胞转运不佳以及抑制T细胞功能的负调控途径的作用已被确定为关键限制因素。重要的负调控途径包括因B7共刺激不足导致的T细胞无反应性、调节性T细胞群体的外在抑制、通过诸如PD-L1等抑制性配体的直接抑制以及通过吲哚胺2,3-双加氧酶活性等导致的代谢失调。对这些逃逸机制的认识为癌症免疫治疗指明了新的治疗方法。
