Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Brain Tumor Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA.
J Immunother Cancer. 2021 Jun;9(6). doi: 10.1136/jitc-2021-002426.
While adoptive transfer of T-cells has been a major medical breakthrough for patients with B cell malignancies, the development of safe and effective T-cell-based immunotherapy for central nervous system (CNS) tumors, such as glioblastoma (GBM), still needs to overcome multiple challenges, including effective homing and persistence of T-cells. Based on previous observations that interleukin (IL)-17-producing T-cells can traffic to the CNS in autoimmune conditions, we evaluated CD8 T-cells that produce IL-17 and interferon-γ (IFN-γ) (Tc17-1) cells in a preclinical GBM model.
We differentiated Pmel-1 CD8 T-cells into Tc17-1 cells and compared their phenotypic and functional characteristics with those of IFN-γ-producing CD8 T (Tc1) and IL-17-producing CD8 T (Tc17) cells. We also evaluated the therapeutic efficacy, persistence, and tumor-homing of Tc17-1 cells in comparison to Tc1 cells using a mouse GL261 glioma model.
In vitro, Tc17-1 cells demonstrated profiles of both Tc1 and Tc17 cells, including production of both IFN-γ and IL-17, although Tc17-1 cells demonstrated lesser degrees of antigen-specific cytotoxic activity compared with Tc1 cells. In mice-bearing intracranial GL261-Quad tumor and treated with temozolomide, Tc1 cells, but not Tc17-1, showed a significant prolongation of survival. However, when the T-cell transfer was combined with poly-ICLC and Pmel-1 peptide vaccine, both Tc1 and Tc17-1 cells exhibited significantly prolonged survival associated with upregulation of very late activation antigen-4 on Tc17-1 cells in vivo. Glioma cells that recurred following the therapy lost the susceptibility to Pmel-1-derived cytotoxic T-cells, indicating that immuno-editing was a mechanism of the acquired resistance.
Tc17-1 cells were equally effective as Tc1 cells when combined with poly-ICLC and peptide vaccine treatment.
过继性转移 T 细胞已经成为 B 细胞恶性肿瘤患者的一项重大医学突破，但对于中枢神经系统（CNS）肿瘤（如胶质母细胞瘤[GBM]），仍需要克服多个挑战才能开发出安全有效的基于 T 细胞的免疫疗法，其中包括 T 细胞的有效归巢和持久性。基于白细胞介素（IL）-17 产生的 T 细胞在自身免疫性疾病中可以转移到中枢神经系统的先前观察结果，我们在一个临床前 GBM 模型中评估了产生 IL-17 和干扰素-γ（IFN-γ）的 CD8 T 细胞（Tc17-1 细胞）。
我们将 Pmel-1 CD8 T 细胞分化为 Tc17-1 细胞，并比较了它们的表型和功能特征与 IFN-γ 产生的 CD8 T（Tc1）和 IL-17 产生的 CD8 T（Tc17）细胞的特征。我们还通过使用小鼠 GL261 神经胶质瘤模型，比较了 Tc17-1 细胞与 Tc1 细胞的治疗效果、持久性和肿瘤归巢情况。
在体外，Tc17-1 细胞表现出 Tc1 和 Tc17 细胞的特征，包括同时产生 IFN-γ和 IL-17，尽管与 Tc1 细胞相比，Tc17-1 细胞表现出较低程度的抗原特异性细胞毒性活性。在接受替莫唑胺治疗的颅内 GL261-Quad 肿瘤荷瘤小鼠中，Tc1 细胞而非 Tc17-1 细胞显示出显著延长的生存时间。然而，当 T 细胞转移与 poly-ICLC 和 Pmel-1 肽疫苗联合使用时，Tc1 和 Tc17-1 细胞均显示出显著延长的生存时间，与体内 Tc17-1 细胞上的非常晚期激活抗原-4 的上调相关。在治疗后复发的神经胶质瘤细胞失去了对 Pmel-1 衍生的细胞毒性 T 细胞的敏感性，表明免疫编辑是获得性耐药的机制之一。
当与 poly-ICLC 和肽疫苗联合使用时，Tc17-1 细胞与 Tc1 细胞同样有效。
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