Wang Yuanshuo A, Ranti Daniel, Bieber Christine, Galsky Matthew, Bhardwaj Nina, Sfakianos John P, Horowitz Amir
The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Bladder Cancer. 2023 Jun 27;9(2):125-139. doi: 10.3233/BLC-220109. eCollection 2023.
For decades, immunotherapies have been integral for the treatment and management of bladder cancer, with immune checkpoint inhibitors (ICIs) transforming patient care in recent years. However, response rates are poor to T cell-targeted ICIs such as programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) blocking antibodies, framing a critical need for complementary immunotherapies. Promising strategies involve harnessing the activation potential of natural killer (NK) cells. They quickly exert their antitumor activity via signaling through germline-encoded activating receptors and are rapidly sensitized to new tissue microenvironments via their regulation by polymorphic HLA class I, KIR and NKG2A receptors.
In this review, we examined the roles of currently available NK-targeted antitumor treatment strategies such as engineered viral vectors, small-molecule IMiDs, NK agonist antibodies, interleukins, and chimeric antigen receptor (CAR) NK cells, and their potential for improving the efficacy of immunotherapy in the treatment of bladder cancer.
Through review of current literature, we summarized our knowledge of NK cells in solid tumors and hematologic malignancies as their roles pertain to novel immunotherapies already being applied to the treatment of bladder cancer or that offer rationale for considering as potential novel immunotherapeutic strategies.
NK cells play a critical role in shaping the tumor microenvironment (TME) that can be exploited to improve T cell-targeted immunotherapies.
Emerging evidence suggests that NK cells are a prime target for improving antitumor functions in immunotherapies for the treatment of bladder cancer. Further research into profiling NK cells in settings of immunotherapies for bladder cancer could help identify patients who might maximally benefit from NK cell-targeted immunotherapies and the various approaches for exploiting their antitumor properties.
几十年来，免疫疗法一直是膀胱癌治疗和管理的重要组成部分，近年来免疫检查点抑制剂（ICI）改变了患者的治疗方式。然而，针对程序性细胞死亡蛋白1（PD-1）和程序性细胞死亡配体1（PD-L1）阻断抗体等T细胞靶向ICI的反应率较低，这凸显了对补充免疫疗法的迫切需求。有前景的策略包括利用自然杀伤（NK）细胞的激活潜力。它们通过种系编码的激活受体发出信号，迅速发挥抗肿瘤活性，并通过多态性HLA I类、杀伤细胞免疫球蛋白样受体（KIR）和NKG2A受体的调节，迅速对新的组织微环境产生敏感性。
在本综述中，我们研究了目前可用的针对NK的抗肿瘤治疗策略的作用，如工程化病毒载体、小分子免疫调节药物（IMiD）、NK激动剂抗体、白细胞介素和嵌合抗原受体（CAR）NK细胞，以及它们在提高免疫疗法治疗膀胱癌疗效方面的潜力。
通过回顾当前文献，我们总结了关于NK细胞在实体瘤和血液系统恶性肿瘤中的作用的知识，因为它们的作用与已经应用于膀胱癌治疗的新型免疫疗法有关，或者为考虑作为潜在的新型免疫治疗策略提供了理论依据。
NK细胞在塑造肿瘤微环境（TME）中起关键作用，可利用这一点来改善T细胞靶向免疫疗法。
新出现的证据表明，NK细胞是改善膀胱癌免疫治疗中抗肿瘤功能的主要靶点。对膀胱癌免疫治疗环境中的NK细胞进行进一步研究，可能有助于识别那些可能从NK细胞靶向免疫治疗中最大程度获益的患者，以及利用其抗肿瘤特性的各种方法。
