Failure at the effector phase: Immune barriers at the level of the melanoma tumor microenvironment
Failure at the effector phase: Immune barriers at the level of the melanoma tumor microenvironment
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DOI：
10.1158/1078-0432.ccr-07-0892
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发表时间：
2007-09-15
影响因子：
11.5
通讯作者：
Gajewski, Thomas F.
中科院分区：
文献类型：
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作者：
Gajewski, Thomas F.
许多治疗性癌症疫苗策略的临床研究结果相对令人失望。虽然少数患者确实经历了临床受益，但大多数患者甚至在血液中很容易检测到诱导功能性肿瘤抗原特异性T细胞反应的情况下也表现出疾病进展。这一观察导致了对肿瘤微环境的询问，以了解肿瘤对抗肿瘤T细胞反应的效应相的潜在耐药机制。趋化因子介导的效应细胞转运不良和抑制T细胞功能的负调控途径的作用已被认为是关键的限制因素。重要的负性调节途径包括T细胞因137共刺激作用不足而产生的无能、调节性T细胞群体的外源性抑制、通过抑制配体如PD-L1的直接抑制、以及代谢失调，如通过吲哚胺2，3-双加氧酶的活性。对这些逃避机制的认识为癌症免疫治疗指明了新的治疗方法。
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 137 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.