Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
Center for Infectious Disease Vaccine and Diagnosis Innovation, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
J Immunother Cancer. 2024 Oct 26;12(10):e009449. doi: 10.1136/jitc-2024-009449.
Certain cancers present challenges for treatment because they are resistant to immune checkpoint blockade (ICB), attributed to low tumor mutational burden and the absence of T cell-inflamed features. Among these, glioblastoma (GBM) is notoriously resistant to ICB. To overcome this resistance, the identification of T cells with heightened stemness marked by T-cell factor 1 (TCF1) expression has gained attention. Several studies have explored ways to preserve stem-like T cells and prevent terminal exhaustion. In this study, we investigate a target that triggers stem-like properties in CD8 T cells to enhance the response to ICB in a murine GBM model.
Using mice and a murine GL261 GBM model, we confirmed the efficacy of anti-programmed cell death protein-1 (PD-1) immunotherapy, observing improved survival. Analysis of immune cells using fluorescence-activated cell sorting and single-cell RNA sequencing delineated distinct subsets of tumor-infiltrating CD8 T cells in mice. The crucial role of the stem-like feature in the response to anti-PD-1 treatment for reinvigorating CD8 T cells was analyzed. Adoptive transfer of OT-I cells into OVA-expressing GL261 models and CD8 T cell depletion in mice confirmed the significance of CD8 T cells in enhancing the antitumor response. Last, S1P inhibitor treatment confirmed that the main source of tumor antigen-specific CD8 T cells is the tumor-draining lymph nodes (TdLNs).
In a murine GBM model, anti-PD-1 monotherapy and single-Fc fragment of IgG receptor IIb (FcγRIIB) deletion exhibit limited efficacy. However, their combination substantially improves survival by enhancing cytotoxicity and proliferative capacity in tumor-infiltrating CD8 T cells. The improved response to anti-PD-1 treatment is associated with the tumor-specific memory T cells (Ttsms) exhibiting high stemness characteristics within the tumor microenvironment (TME). Ttsms in the TdLN thrives in a protective environment, maintaining stem-like characteristics and serving as a secure source for tumor infiltration. This underscores the significance of FcγRIIB ablation in triggering Ttsms and enhancing ICB therapy against GBM.
Deletion of FcγRIIB on CD8 T cells leads to the generation of a Ttsms, which is localized in TdLN and protected from the immunosuppressive TME. Incorporating these highly stemness-equipped Ttsms enhances the response to anti-PD-1 therapy in immune-suppressed brain tumors.
某些癌症在治疗方面具有挑战性，因为它们对免疫检查点阻断（ICB）具有抗性，这归因于低肿瘤突变负担和缺乏 T 细胞浸润特征。其中，胶质母细胞瘤（GBM）对 ICB 的抗性尤为明显。为了克服这种抗性，人们已经注意到具有 T 细胞因子 1（TCF1）表达标记的高度干性的 T 细胞的鉴定。已经有几项研究探讨了保存类干细胞 T 细胞和防止终末衰竭的方法。在这项研究中，我们研究了一个在小鼠 GBM 模型中触发 CD8 T 细胞类干细胞特性的靶点，以增强对 ICB 的反应。
使用 小鼠和 GL261 GBM 模型，我们证实了抗程序性细胞死亡蛋白-1（PD-1）免疫疗法的疗效，观察到生存率提高。使用荧光激活细胞分选和单细胞 RNA 测序对免疫细胞进行分析，描绘了 小鼠中浸润性肿瘤 CD8 T 细胞的不同亚群。分析了抗 PD-1 治疗对重新激活 CD8 T 细胞的反应中类干细胞特征的关键作用。将 OT-I 细胞过继转移到表达 OVA 的 GL261 模型中，并在 小鼠中耗尽 CD8 T 细胞，证实了 CD8 T 细胞在增强抗肿瘤反应中的重要性。最后，S1P 抑制剂治疗证实，肿瘤抗原特异性 CD8 T 细胞的主要来源是肿瘤引流淋巴结（TdLNs）。
在 GBM 模型中，抗 PD-1 单药治疗和 IgG 受体 IIb 的单 Fc 片段（FcγRIIB）缺失的疗效有限。然而，它们的联合使用通过增强浸润性肿瘤的 CD8 T 细胞的细胞毒性和增殖能力，显著提高了生存率。对抗 PD-1 治疗的反应改善与肿瘤特异性记忆 T 细胞（Ttsms）有关，其在肿瘤微环境（TME）中表现出高度干性特征。在 TdLN 中，Ttsms 在保护性环境中茁壮成长，保持类干细胞特征，并作为肿瘤浸润的安全来源。这突出了在 CD8 T 细胞上缺失 FcγRIIB 以触发 Ttsms 和增强针对 GBM 的 ICB 治疗的重要性。
CD8 T 细胞上 FcγRIIB 的缺失导致 Ttsms 的产生，其定位于 TdLN 并受到免疫抑制性 TME 的保护。纳入这些具有高度干性的 Ttsms 可增强免疫抑制性脑肿瘤对抗 PD-1 治疗的反应。
