Zhang Cai, Hu Yuan, Shi Chongdeng
Institute of Immunopharmaceutical Sciences, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, China.
Front Immunol. 2020 Feb 19;11:60. doi: 10.3389/fimmu.2020.00060. eCollection 2020.
Natural killer (NK) cells are important innate cytotoxic lymphocytes with a rapid and efficient capacity to recognize and kill tumor cells. In recent years, adoptive transfer of autologous- or allogeneic-activated NK cells has become a promising cellular therapy for cancer. However, the therapeutic efficiency is encouraging in hematopoietic malignancies, but disappointing in solid tumors, for which the use of NK-cell-based therapies presents considerable challenges. It is difficult for NK cells to traffic to, and infiltrate into, tumor sites. NK cell function, phenotype, activation, and persistence are impaired by the tumor microenvironment, even leading to NK cell dysfunction or exhaustion. Many strategies focusing on improving NK cells' durable persistence, activation, and cytolytic activity, including activation with cytokines or analogs, have been attempted. Modifying them with chimeric antigen receptors further increases the targeting specificity of NK cells. Checkpoint blockades can relieve the exhausted state of NK cells. In this review, we discuss how the cytolytic and effector functions of NK cells are affected by the tumor microenvironment and summarize the various immunotherapeutic strategies based on NK cells. In particular, we discuss recent advances in overcoming the suppressive effect of the tumor microenvironment with the aim of enhancing the clinical outcome in solid tumors treated with NK-cell-based immunotherapy.
自然杀伤（NK）细胞是重要的先天性细胞毒性淋巴细胞，具有快速高效识别和杀伤肿瘤细胞的能力。近年来，自体或异体活化NK细胞的过继性转移已成为一种很有前景的癌症细胞疗法。然而，这种疗法在血液系统恶性肿瘤中的治疗效果令人鼓舞，但在实体瘤中却令人失望，基于NK细胞的疗法在实体瘤治疗中面临着诸多挑战。NK细胞很难迁移至肿瘤部位并浸润其中。肿瘤微环境会损害NK细胞的功能、表型、活化及持久性，甚至导致NK细胞功能障碍或耗竭。人们尝试了许多策略来提高NK细胞的持久存续、活化及细胞溶解活性，包括用细胞因子或类似物进行活化。用嵌合抗原受体对其进行改造可进一步提高NK细胞的靶向特异性。检查点阻断可缓解NK细胞的耗竭状态。在本综述中，我们讨论了肿瘤微环境如何影响NK细胞的细胞溶解和效应功能，并总结了基于NK细胞的各种免疫治疗策略。特别是，我们讨论了在克服肿瘤微环境抑制作用方面的最新进展，旨在提高基于NK细胞的免疫疗法治疗实体瘤的临床疗效。
