自然杀伤 (NK) 细胞是重要的先天免疫参与者，具有识别和消除癌细胞的独特能力，特别是在抗体调理作用和抗体依赖性细胞毒性 (ADCC) 的情况下。然而，膀胱癌中 NK 细胞对治疗性抗体的反应通常受到免疫抑制，而这些免疫抑制机制在很大程度上是未知的。 单细胞 RNA 测序 (scRNA-seq) 和高维流式细胞术用于研究肿瘤浸润的表型膀胱癌患者的 NK 细胞。此外，该疾病的体外和体内模型被用来验证这些发现。膀胱肿瘤内的 NK 细胞在转录和蛋白质水平上表现出 FcγRIIIa/CD16 的表达减少，FcγRIIIa/CD16 是参与 ADCC 介导的细胞毒性的关键 Fc 受体。转化生长因子 (TGF)-β-信号传导是一种多效性细胞因子，以其免疫抑制和组织驻留诱导作用而闻名，其转录特征在肿瘤浸润 NK 细胞中上调。 TGF-β 介导的 NK 细胞 CD16 下调在体外得到了进一步验证，同时伴随着向组织驻留表型的转变。这种 CD16 下调也被 TGF-βR 信号传导抑制所消除，这也可以恢复受 TGF-β 影响的 NK 细胞的 ADCC 能力。在膀胱癌人源化小鼠模型中，与仅用抗体治疗的小鼠相比，用 TGF-β 抑制剂治疗的小鼠表现出更高的 ADCC 活性。这项研究强调了富含 TGF-β 的膀胱癌如何通过下调 CD16 来抑制 NK 细胞介导的 ADCC。 TGF-β 抑制代表了逆转免疫抑制和增强膀胱癌 NK 细胞杀肿瘤能力的新途径。吉马良斯实验室由美国国防部乳腺癌研究计划突破奖 1 级 (#BC200025) 资助(#2019485) 通过医学研究未来基金 (MRFF，在昆士兰儿童医院基金会、Microba Life Sciences、Richie's Rainbow 基金会、转化研究所 (TRI) 和 UQ 的支持下）授予，并获得一笔赠款 (#RSS_2023_085)由 Metro South 健康研究支持计划提供。 J.K.M.W.由昆士兰大学研究培训计划博士奖学金和 N.O. 资助。由 NHMRC 研究生奖学金 (#2021932) 资助。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Natural killer (NK) cells are important innate immunity players and have unique abilities to recognize and eliminate cancer cells, particularly in settings of antibody-opsonization and antibody-dependant cellular cytotoxicity (ADCC). However, NK cell-based responses in bladder cancers to therapeutic antibodies are typically immunosuppressed, and these immunosuppressive mechanisms are largely unknown.Single cell RNA sequencing (scRNA-seq) and high-dimensional flow cytometry were used to investigate the phenotype of tumour-infiltrating NK cells in patients with bladder cancer. Further, in vitro, and in vivo models of this disease were used to validate these findings.NK cells within bladder tumours displayed reduced expression of FcγRIIIa/CD16, the critical Fc receptor involved in ADCC-mediated cytotoxicity, on both transcriptional and protein levels. Transcriptional signatures of transforming growth factor (TGF)-β-signalling, a pleiotropic cytokine known for its immunosuppressive and tissue residency-inducing effects, were upregulated in tumour-infiltrating NK cells. TGF-β mediated CD16 downregulation on NK cells, was further validated in vitro, which was accompanied by a transition into a tissue residency phenotype. This CD16 downregulation was also abrogated by TGF-βR signalling inhibition, which could also restore the ADCC ability of NK cells subject to TGF-β effects. In a humanized mouse model of bladder cancer, mice treated with a TGF-β inhibitor exhibited increased ADCC activity compared to mice treated only with antibodies.This study highlights how TGF-β-rich bladder cancers inhibit NK cell-mediated ADCC by downregulating CD16. TGF-β inhibition represents new avenues to reverse immunosuppression and enhance the tumoricidal capacity of NK cells in bladder cancer.The Guimaraes Laboratory is funded by a US Department of Defense-Breast Cancer Research Program-Breakthrough Award Level 1 (#BC200025), a grant (#2019485) awarded through the Medical Research Future Fund (MRFF, with the support of the Queensland Children's Hospital Foundation, Microba Life Sciences, Richie's Rainbow Foundation, Translational Research Institute (TRI) and UQ), and a grant (#RSS_2023_085) funded by a Metro South Health Research Support Scheme. J.K.M.W. is funded by a UQ Research Training Program PhD Scholarship and N.O. is funded by a NHMRC Postgraduate Scholarship (#2021932).Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.