How Do Cytotoxic Lymphocytes Kill Cancer Cells?
How Do Cytotoxic Lymphocytes Kill Cancer Cells?
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DOI：
10.1158/1078-0432.ccr-15-0685
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发表时间：
2015-11-15
影响因子：
11.5
通讯作者：
Pardo, Julian
中科院分区：
文献类型：
--
作者：
Martinez-Lostao, Luis;Anel, Alberto;Pardo, Julian
在过去的几年中，癌症免疫疗法已成为一种安全有效的替代疗法，用于治疗对经典疗法没有反应的癌症，包括那些具有高侵袭性的类型。新的免疫调节剂，如细胞因子、CTLA-4（细胞毒性 T 淋巴细胞相关蛋白 4）和 PD-1（程序性细胞死亡蛋白 1）/PD-L1（程序性死亡配体 1）阻断剂以及相互作用或过继细胞疗法，已被开发并批准用于治疗实体癌和血液癌。在这些情况下，细胞毒性淋巴细胞 (CL)，主要是细胞毒性 T 细胞 (Tc) 和自然杀伤 (NK) 细胞，最终负责杀死癌细胞并根除肿瘤。人们已经进行了大量研究来评估 Tc 和 NK 细胞如何被激活并识别癌细胞。相比之下，很少有研究关注 CL 在癌症免疫监视和免疫治疗过程中用来杀死癌细胞的效应分子。本文简要介绍了 CL 介导的肿瘤细胞死亡的两个主要途径，即颗粒胞吐作用（穿孔素和颗粒酶）和死亡配体，然后对癌症免疫监视和免疫治疗过程中参与细胞死亡的分子进行了批判性讨论。本讨论还涵盖了颗粒酶和死亡配体的促炎和生存作用的意外后果，以及最近的实验证据表明穿孔素和 CL 颗粒酶可以激活细胞死亡的非凋亡途径，克服细胞凋亡缺陷和化疗耐药性。还简要讨论了细胞凋亡与其他细胞死亡方式对于通过调节患者免疫系统有效治疗癌症的影响。 (C) 2015 年 AACR。
In the past few years, cancer immunotherapy has emerged as a safe and effective alternative for treatment of cancers that do not respond to classical treatments, including those types with high aggressiveness. New immune modulators, such as cytokines, blockers of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1(programmed cell death protein 1)/PD-L1 (programmed death-ligand 1), and interaction or adoptive cell therapy, have been developed and approved to treat solid and hematologic carcinomas. In these scenarios, cytotoxic lymphocytes (CL), mainly cytotoxic T cells (Tc) and natural killer (NK) cells, are ultimately responsible for killing the cancer cells and eradicating the tumor. Extensive studies have been conducted to assess how Tc and NK cells get activated and recognize the cancer cell. In contrast, few studies have focused on the effector molecules used by CLs to kill cancer cells during cancer immunosurveillance and immunotherapy. In this article, the two main pathways involved in CL-mediated tumor cell death, granule exocytosis (perforin and granzymes) and death ligands, are briefly introduced, followed by a critical discussion of the molecules involved in cell death during cancer immunosurveillance and immunotherapy. This discussion also covers unexpected consequences of proinflammatory and survival effects of granzymes and death ligands and recent experimental evidence indicating that perforin and granzymes of CLs can activate nonapoptotic pathways of cell death, overcoming apoptosis defects and chemoresistance. The consequences of apoptosis versus other modalities of cell death for an effective treatment of cancer by modulating the patient immune system are also briefly discussed. (C) 2015 AACR.