IL-21 通过增殖 PD-1intTim-3-CD8+ T 细胞来靶向肿瘤，重塑肿瘤微环境。
Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3-CD8+ T cells.
机构信息
Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
出版信息
JCI Insight. 2020 Apr 9;5(7):132000. doi: 10.1172/jci.insight.132000.
The lack of sufficient functional tumor-infiltrating lymphocytes in the tumor microenvironment (TME) is one of the primary indications for the poor prognosis of patients with cancer. In this study, we developed an Erbitux-based IL-21 tumor-targeting fusion protein (Erb-IL21) to prolong the half-life and improve the antitumor efficacy of IL-21. Compared with Erb-IL2, Erb-IL21 demonstrated much lower toxicity in vivo. Mechanistically, Erb-IL21 selectively expanded functional cytotoxic T lymphocytes but not dysfunctional CD8+ T cells in the TME. We observed that the IL-21-mediated antitumor effect largely depended on the existing intratumoral CD8+ T cells, instead of newly migrated CD8+ T cells. Furthermore, Erb-IL21 overcame checkpoint blockade resistance in mice with advanced tumors. Our study reveals that Erb-IL21 can target IL-21 to tumors and maximize the antitumor potential of checkpoint blockade by expending a subset of tumor antigen-specific CD8+ T cells to achieve effective tumor control.
肿瘤微环境（TME）中缺乏足够的功能性肿瘤浸润淋巴细胞是癌症患者预后不良的主要原因之一。在这项研究中，我们开发了一种基于爱必妥的 IL-21 肿瘤靶向融合蛋白（Erb-IL21），以延长 IL-21 的半衰期并提高其抗肿瘤疗效。与 Erb-IL2 相比，Erb-IL21 在体内的毒性要低得多。在机制上，Erb-IL21 选择性地扩增了 TME 中功能正常的细胞毒性 T 淋巴细胞，而不是功能失调的 CD8+T 细胞。我们观察到，IL-21 介导的抗肿瘤作用在很大程度上取决于肿瘤内已存在的 CD8+T 细胞，而不是新迁移的 CD8+T 细胞。此外，Erb-IL21 克服了晚期肿瘤小鼠的检查点阻断耐药性。我们的研究表明，Erb-IL21 可以将 IL-21 靶向肿瘤，并通过扩展一部分肿瘤抗原特异性 CD8+T 细胞来最大限度地发挥检查点阻断的抗肿瘤潜力，从而实现有效的肿瘤控制。
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