Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center , Dallas, TX, USA.
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center , Dallas, TX, USA.
J Exp Med. 2024 Dec 2;221(12). doi: 10.1084/jem.20240797. Epub 2024 Oct 29.
Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression. H2-Aa deficiency, specifically in dendritic cells (DC), led to a quantitative increase in type 2 conventional DC (cDC2) and a decrease in cDC1. H2-Aa-deficient cDC2, but not cDC1, were essential for melanoma suppression and effectively cross-primed and recruited CD8 T cells into tumors. Lack of T regulatory cells, also observed in H2-Aa deficiency, contributed to melanoma suppression. Acute disruption of H2-Aa was therapeutic in melanoma-bearing mice, particularly when combined with checkpoint inhibition, which had no therapeutic effect by itself. Our findings suggest that inhibiting MHC-II may be an effective immunotherapeutic approach to enhance immune responses to cancer.
免疫检查点抑制剂会干扰 T 细胞衰竭，但在患者中长期内往往无法治愈或控制癌症。我们在 C57BL/6J 小鼠中使用基因筛选发现，宿主 H2-Aa 的突变导致其强烈的免疫介导的抵抗小鼠黑色素瘤。H2-Aa 编码 MHC Ⅱ类 α 链，而 C57BL/6J 小鼠中其缺失会消除所有 MHC-II 表达。H2-Aa 缺陷，特别是在树突状细胞（DC）中，导致 2 型常规 DC（cDC2）的数量增加，而 cDC1 减少。H2-Aa 缺陷的 cDC2，而不是 cDC1，对黑色素瘤的抑制至关重要，并且可以有效地交叉呈递和招募 CD8 T 细胞进入肿瘤。在 H2-Aa 缺陷中也观察到 T 调节细胞的缺乏，这有助于黑色素瘤的抑制。在患有黑色素瘤的小鼠中，急性破坏 H2-Aa 具有治疗作用，尤其是与检查点抑制联合使用时，单独使用检查点抑制没有治疗效果。我们的研究结果表明，抑制 MHC-II 可能是增强对癌症免疫反应的有效免疫治疗方法。
