免疫检查点分子与天然免疫稳态调控
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摘要
近年来以免疫检查点分子PD-1、CTLA-4为靶点的免疫干预策略为相关疾病的诊治带来了新的希望。目前Tim-3、LAG-3及TIGIT等免疫相关分子被认为是最具潜力的新一代免疫治疗靶点,其相关药物研究也已经进入Ⅱ期或Ⅲ期临床研究阶段。大多数的研究重点关注免疫检查点分子对T细胞耐受的影响,而近来的研究表明Tim-3、PD-1等免疫检查点分子在天然免疫稳态调控中也发挥至关重要的作用。天然免疫细胞通过调控微环境影响或决定特异性免疫应答的方向及结局,靶向天然免疫细胞的干预策略越来越受到人们的重视。针对免疫检查点分子的干预策略如何或在多大程度上影响天然免疫细胞稳态是非常值得探讨的课题。本综述主要阐述Tim-3等免疫检查点分子调控天然免疫稳态的机制及意义,一方面旨在更全面地了解该类免疫检查点分子的作用机制,另一方面也为拓展该类靶点的临床应用提供新依据。
The immune intervention strategy targeting the immune checkpoints such as PD-1 and CTLA-4 has brought new hopes for the treatment of immune disorders. Recently,immune checkpoint inhibitors including Tim-3,LAG-3 and TIGIT are considered as new generation of potential therapeutic targets,and antagonists against these checkpoints are now in phase Ⅰ or phase Ⅱ clinical trials. Most studies focus on the effects of immune checkpoint molecules on T cell tolerance. However,more and more reports have shown that immune checkpoint inhibitors such as PD-1,Tim-3 also play crucial roles in maintaining innate immune homeostasis. Innate immune cells play critical roles in manipulating the local microenvironment and in determining the outcome of adaptive immunity. Strategies targeting innate immune cells have attracted considerable attention in the fields of immunotherapy. How and to what extent,immune check point interventions modulate innate immune responses are largely unknown. This review focuses on the mechanisms and the possible implications of Tim-3 and other immune checkpoints regulated innate immune responses,aiming to fully understand the regulatory roles of immune checkpoints and to provide new lights on immunotherapy strategies.
The immune intervention strategy targeting the immune checkpoints such as PD-1 and CTLA-4 has brought new hopes for the treatment of immune disorders. Recently,immune checkpoint inhibitors including Tim-3,LAG-3 and TIGIT are considered as new generation of potential therapeutic targets,and antagonists against these checkpoints are now in phase Ⅰ or phase Ⅱ clinical trials. Most studies focus on the effects of immune checkpoint molecules on T cell tolerance. However,more and more reports have shown that immune checkpoint inhibitors such as PD-1,Tim-3 also play crucial roles in maintaining innate immune homeostasis. Innate immune cells play critical roles in manipulating the local microenvironment and in determining the outcome of adaptive immunity. Strategies targeting innate immune cells have attracted considerable attention in the fields of immunotherapy. How and to what extent,immune check point interventions modulate innate immune responses are largely unknown. This review focuses on the mechanisms and the possible implications of Tim-3 and other immune checkpoints regulated innate immune responses,aiming to fully understand the regulatory roles of immune checkpoints and to provide new lights on immunotherapy strategies.
引文
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[34]Yang X,Jiang X,Chen G,et al.T cell Ig mucin-3 promotes homeostasis of sepsis by negatively regulating the TLR response[J].JImmunol,2013,190(5):2068-2079.
[35]Li X,Chen G,Li Y,et al.Involvement of T cell Ig Mucin-3(Tim-3)in the negative regulation of inflammatory bowel disease[J].Clin Immunol,2010,134(2):169-177.
[36]Jiang X,Zhou T,Xiao Y,et al.Tim-3 promotes tumor-promoting M2 macrophage polarization by binding to STAT1 and suppressing the STAT1-miR-155 signaling axis[J].Oncoimmunology,2016,5(9):e1211219.
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[40]Wang Z,Sun D,Chen G,et al.Tim-3 inhibits macrophage control of Listeria monocytogenes by inhibiting Nrf2[J].Sci Rep,2017,7:42095.
[41]Li X,Wang B,Gu L,et al.Tim-3 expression predicts the abnormal innate immune status and poor prognosis of glioma patients[J].Clin Chim Acta,2018,476:178-184.
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