Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USA.
Commun Biol. 2023 Apr 25;6(1):447. doi: 10.1038/s42003-023-04812-3.
Efficacy of immune checkpoint inhibitors in cancers can be limited by CD8 T cell dysfunction or HLA-I down-regulation. Tumor control mechanisms independent of CD8/HLA-I axis would overcome these limitations. Here, we report potent CD4 T cell-mediated tumor regression and memory responses in humanized immune system (HIS) mice implanted with HT-29 colorectal tumors. The regressing tumors showed increased CD4 cytotoxic T lymphocyte (CTL) infiltration and enhanced tumor HLA-II expression compared to progressing tumors. The intratumoral CD4 T cell subset associated with tumor regression expressed multiple cytotoxic markers and exhibited clonal expansion. Notably, tumor control was abrogated by depletion of CD4 but not CD8 T cells. CD4 T cells derived from tumor-regressing mice exhibited HLA-II-dependent and tumor-specific killing ex vivo. Taken together, our study demonstrates a critical role of human CD4 CTLs in mediating tumor clearance independent of CD8 T cells and provides a platform to study human anti-tumor immunity in vivo.
免疫检查点抑制剂在癌症中的疗效可能受到 CD8 T 细胞功能障碍或 HLA-I 下调的限制。独立于 CD8/HLA-I 轴的肿瘤控制机制将克服这些限制。在这里，我们报告了在植入 HT-29 结直肠肿瘤的人源化免疫系统 (HIS) 小鼠中，强大的 CD4 T 细胞介导的肿瘤消退和记忆反应。与进展性肿瘤相比，消退的肿瘤显示出增加的 CD4 细胞毒性 T 淋巴细胞 (CTL) 浸润和增强的肿瘤 HLA-II 表达。与肿瘤消退相关的肿瘤内 CD4 T 细胞亚群表达多种细胞毒性标志物，并表现出克隆扩增。值得注意的是，CD4 但不是 CD8 T 细胞的耗竭会破坏肿瘤控制。来自肿瘤消退小鼠的 CD4 T 细胞表现出 HLA-II 依赖性和肿瘤特异性杀伤作用。综上所述，我们的研究表明，人类 CD4 CTL 在介导独立于 CD8 T 细胞的肿瘤清除中起着关键作用，并为体内研究人类抗肿瘤免疫提供了一个平台。
