Harrer Dennis Christoph, Schlierkamp-Voosen Tim, Barden Markus, Pan Hong, Xydia Maria, Herr Wolfgang, Dörrie Jan, Schaft Niels, Abken Hinrich
Department of Internal Medicine III-Hematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, Germany.
Leibniz Institute for Immunotherapy, Division Genetic Immunotherapy, University Regensburg, 93053 Regensburg, Germany.
Cells. 2025 Jun 14;14(12):901. doi: 10.3390/cells14120901.
T cells equipped with chimeric antigen receptors (CARs) have evolved into an essential pillar of lymphoma therapy, reaching second-line treatment. In solid cancers, however, a dearth of lasting CAR T cell activation poses the major obstacle to achieving a substantial and durable anti-tumor response. To extend T cell cytotoxic capacities, we engineered CAR T cells to constitutively release an immunostimulatory variant of soluble SLAMF6. While wild-type SLAMF6 induces T cell exhaustion, CAR T cells with the soluble Δ17-65 SLAMF6 variant exhibited refined, CAR redirected functionality compared to canonical CAR T cells. CD28-ζ CAR T cells releasing soluble SLAMF6 increased IFN-γ secretion and augmented CD25 upregulation on CD4 CAR T cells upon CAR engagement by pancreatic carcinoma and melanoma cells. Moreover, under conditions of repetitive antigen encounter, SLAMF6-secreting CAR T cells evinced superior cytotoxic capacity in the long term. Mechanistically, SLAMF6-secreting CAR T cells showed predominantly a central memory phenotype, a PD-1 TIGIT double negative profile, and reduced expression of exhaustion-related transcription factors IRF-4 and TOX with augmented amplification and persistence capacities. Overall, CAR T cells engineered with the release isoform 2 SLAMF6 establish an auto-stimulatory loop with the potential to boost the cytolytic attack against solid tumors.
配备嵌合抗原受体（CAR）的T细胞已发展成为淋巴瘤治疗的重要支柱，进入二线治疗。然而，在实体癌中，缺乏持久的CAR T细胞激活是实现实质性和持久抗肿瘤反应的主要障碍。为了扩展T细胞的细胞毒性能力，我们对CAR T细胞进行了工程改造，使其组成性释放可溶性SLAMF6的免疫刺激变体。虽然野生型SLAMF6会诱导T细胞耗竭，但与经典CAR T细胞相比，携带可溶性Δ17-65 SLAMF6变体的CAR T细胞表现出更精细的、由CAR重定向的功能。释放可溶性SLAMF6的CD28-ζ CAR T细胞在胰腺癌和黑色素瘤细胞与CAR结合后，增加了IFN-γ分泌，并增强了CD4 CAR T细胞上CD25的上调。此外，在反复接触抗原的条件下，分泌SLAMF6的CAR T细胞长期表现出更强的细胞毒性能力。从机制上讲，分泌SLAMF6的CAR T细胞主要表现为中央记忆表型、PD-1 TIGIT双阴性特征，以及与耗竭相关的转录因子IRF-4和TOX的表达降低，同时扩增和持久能力增强。总体而言，用释放异构体2 SLAMF6工程改造的CAR T细胞建立了一个自刺激环，有可能增强对实体瘤的溶细胞攻击。
