Suppression of melanoma by mice lacking MHC-II: mechanisms and implications for cancer immunotherapy

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. WT or H2-Aa deficient (cit) splenic DC were enriched from splenocyte suspensions using EasySep Mouse CD11c Positive Selection Kit. Then, CD45.2+ CD11c+ cells were FACS sorted for scRNA-seq.

免疫检查点抑制剂（immune checkpoint inhibitors）可抑制T细胞耗竭，但往往无法长期治愈或控制患者体内的癌症。本研究通过对C57BL/6J小鼠开展遗传筛选，发现宿主的H2-Aa基因发生突变后，可使小鼠对黑色素瘤产生强烈的免疫介导抗性。H2-Aa编码主要组织相容性复合体II类α链（MHC class II α chain），在C57BL/6J小鼠中H2-Aa的缺失会彻底消除所有MHC-II的表达。H2-Aa基因缺失，尤其是在树突状细胞（dendritic cells, DC）中的缺失，会导致2型常规树突状细胞（cDC2）的数量增加，同时减少1型常规树突状细胞（cDC1）的数量。H2-Aa缺失的cDC2（而非cDC1）是抑制黑色素瘤的关键，可有效交叉致敏并招募CD8+ T细胞进入肿瘤微环境。H2-Aa缺失还会导致调节性T细胞（T regulatory cells）减少，这同样有助于黑色素瘤的抑制。急性敲除H2-Aa基因对荷黑色素瘤小鼠具有治疗效果，尤其是与免疫检查点抑制联合使用时——而单独使用免疫检查点抑制并无治疗效果。本研究结果表明，抑制MHC-II或许可成为增强机体抗肿瘤免疫应答的有效免疫治疗策略。我们使用EasySep小鼠CD11c阳性分选试剂盒（EasySep Mouse CD11c Positive Selection Kit）从脾细胞悬液中富集野生型（WT）或H2-Aa缺失型（cit）脾脏树突状细胞。随后，通过荧光激活细胞分选（FACS）分选出CD45.2+ CD11c+ 细胞，用于单细胞RNA测序（scRNA-seq）。