人源化肿瘤模型对于癌症免疫治疗研究特别有价值，因为它们可以更好地反映肿瘤与人类癌症免疫系统之间界面的人类特异性方面。然而，人源化模型中的内源性抗肿瘤免疫在很大程度上仍不清楚。我们利用来自造血祖细胞的人类免疫细胞和转化自体B细胞产生的肿瘤重建的NSG小鼠建立了自体人源化小鼠肿瘤模型。我们展示了皮下植入后实体淋巴肿瘤的生长、内源性人类免疫细胞的浸润以及模型的免疫能力。我们发现了人类癌症中描述的人类 T 细胞亚群，包括祖细胞耗尽 (Tpex)、终末耗尽 (Tex-term) 和组织-荷瘤人源化小鼠体内的驻留（TRM）细胞，肿瘤中 Tex-term 和 TRM 积累。此外，我们通过 CD137 的表达鉴定了肿瘤反应性 CD8 T 细胞。这种从头产生的人类 CD137 CD8 T 细胞亚群表现出高度增殖、完全激活的效应子和耗竭样表型，并增强了激活和耗竭标记物的表达，如 PD-1、CD39、CD160、TIM-3、TIGIT 和 TOX，衰老标记物 CD57 (B3GAT1) 和细胞溶解效应分子，例如 PRF1、GZMH 和 NKG7。此外，这些 CD137 CD8 T 细胞表现出肿瘤特异性克隆扩增，并与人类癌症中描述的肿瘤反应性 CD8 T 细胞表现出特征重叠。我们通过使用携带自体人类肿瘤的受体进行过继转移实验，证明了这种激活且耗尽的人类 CD8 T 细胞亚群具有卓越的抗癌活性。过继转移CD137 CD8 T细胞的小鼠表现出肿瘤生长减少和CD8 T细胞肿瘤浸润增加，这与人类肿瘤的控制相关。我们建立了具有免疫活性的人源化肿瘤模型，为免疫治疗研究提供了工具，并确定了人效应子CD8的有效抗癌活性具有激活和耗尽样表型的 T 细胞，支持过继性 T 细胞疗法中此类细胞的临床探索。瑞士癌症研究基金会。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Humanized tumour models could be particularly valuable for cancer immunotherapy research, as they may better reflect human-specific aspects of the interfaces between tumour and immune system of human cancer. However, endogenous antitumour immunity in humanized models is still largely undefined.We established an autologous humanized mouse tumour model by using NSG mice reconstituted with human immune cells from hematopoietic progenitors and tumours generated from transformed autologous human B cells. We demonstrate growth of solid lymphoid tumours after subcutaneous implantation, infiltration by endogenous human immune cells and immunocompetence of the model.We found human T cell subsets described in human cancer, including progenitor exhausted (Tpex), terminally exhausted (Tex-term) and tissue-resident (TRM) cells in tumour-bearing humanized mice with accumulation of Tex-term and TRM in the tumour. In addition, we identified tumour-reactive CD8+ T cells through expression of CD137. This subpopulation of de novo arising human CD137+ CD8+ T cells displayed a highly proliferative, fully activated effector and exhausted-like phenotype with enhanced expression of activation and exhaustion markers like PD-1, CD39, CD160, TIM-3, TIGIT and TOX, the senescence marker CD57 (B3GAT1) and cytolytic effector molecules such as PRF1, GZMH and NKG7. Moreover, these CD137+ CD8+ T cells exhibited tumour-specific clonal expansion and presented signature overlap with tumour-reactive CD8+ T cells described in human cancer. We demonstrate superior anticancer activity of this activated and exhausted-like human CD8+ T cell subset by adoptive transfer experiments using recipients bearing autologous human tumours. Mice adoptively transferred with CD137+ CD8+ T cells showed reduced tumour growth and higher CD8+ T cell tumour infiltration, correlating with control of human tumours.We established an immunocompetent humanized tumour model, providing a tool for immunotherapy research and defined effective anticancer activity of human effector CD8+ T cells with an activated and exhausted-like phenotype, supporting clinical exploration of such cells in adoptive T cell therapies.Swiss Cancer Research foundation.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.