Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, USA; Graduate Program in Cellular and Molecular Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.
Division of Surgical Oncology, Department of Surgery, Rush University Medical Center, Chicago, Illinois, USA.
J Invest Dermatol. 2023 Oct;143(10):2007-2018.e6. doi: 10.1016/j.jid.2023.03.1664. Epub 2023 Mar 29.
Mouse models that reflect human disorders provide invaluable tools for the translation of basic science discoveries to clinical therapies. However, many of these in vivo therapeutic studies are short term and do not accurately mimic patient conditions. In this study, we used a fully immunocompetent, transgenic mouse model, TGS, in which the spontaneous development of metastatic melanoma is driven by the ectopic expression of a normal neuronal receptor, mGluR1, as a model to assess longitudinal treatment response (up to 8 months) with an inhibitor of glutamatergic signaling, troriluzole, which is a prodrug of riluzole, plus an antibody against PD-1, an immune checkpoint inhibitor. Our results reveal a sex-biased treatment response that led to improved survival in troriluzole and/or anti-PD-1-treated male mice that correlated with differential CD8 T cells and CD11b myeloid cell populations in the tumor-stromal interface, supporting the notion that this model is a responsive and tractable system for evaluating therapeutic regimens for melanoma in an immunocompetent setting.
反映人类疾病的小鼠模型为将基础科学发现转化为临床治疗提供了宝贵的工具。然而，这些体内治疗研究中的许多都是短期的，无法准确模拟患者的情况。在这项研究中，我们使用了一种完全免疫功能正常的转基因小鼠模型 TGS，其中转移性黑色素瘤的自发发展是由正常神经元受体 mGluR1 的异位表达驱动的，该模型用于评估谷氨酸能信号抑制剂 troriluzole（利鲁唑的前药）联合抗 PD-1 抗体（一种免疫检查点抑制剂）的纵向治疗反应（长达 8 个月）。我们的结果揭示了一种性别偏倚的治疗反应，导致接受 troriluzole 和/或抗 PD-1 治疗的雄性小鼠的生存率提高，这与肿瘤基质界面中差异的 CD8 T 细胞和 CD11b 髓样细胞群相关，支持了这样一种观点，即该模型是一个有反应性和可操作性的系统，可用于评估免疫功能正常的黑色素瘤的治疗方案。
