CD4 T Cell-Dependent Rejection of Beta-2 Microglobulin Null Mismatch Repair-Deficient Tumors
CD4 T Cell-Dependent Rejection of Beta-2 Microglobulin Null Mismatch Repair-Deficient Tumors
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DOI：
10.1158/2159-8290.cd-20-0987
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发表时间：
2021-07-01
期刊：
影响因子：
28.2
通讯作者：
Bardelli, Alberto
中科院分区：
文献类型：
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作者：
Germano, Giovanni;Lu, Steve;Bardelli, Alberto
β-2微球蛋白（B2 M）的失活被认为是黑色素瘤和肺癌对免疫检查点抑制剂（ICPi）耐药性的决定因素。相比之下，B2 M丢失似乎不影响错配修复缺陷（MMRd）结直肠肿瘤中对ICP的反应，其中经常观察到B2 M的双等位基因失活。我们在多种鼠MMRd癌症模型中灭活了B2 m。尽管MMRd细胞不易于在免疫活性小鼠中生长，但MMRd B2 m缺失细胞具有致瘤性，并且在用抗PD-1和抗CTLA 4处理时消退。ICPis对MMRd B2 m无效肿瘤的疗效不需要CD 8（+）T细胞，但依赖于CD 4（+）T细胞的存在。表达低水平B2 M的人类肿瘤显示肿瘤内CD 4（+）T细胞增加。我们的结论是，B2 M失活并不钝化的疗效ICPi在MMRd肿瘤，我们确定了一个独特的作用，CD 4（+）T细胞在肿瘤rejecting.Significance：B2 M的改变，这损害抗原呈递，经常发生在微卫星不稳定的结直肠癌。虽然在黑色素瘤和肺癌中B2 M丢失是对免疫检查点阻断的抵抗机制，但我们表明MMRd肿瘤通过CD 4（+）T细胞活化对ICP作出反应。
Inactivation of beta-2 microglobulin (B2M) is considered a determinant of resistance to immune checkpoint inhibitors (ICPi) in melanoma and lung cancers. In contrast, B2M loss does not appear to affect response to ICPis in mismatch repair-deficient (MMRd) colorectal tumors where biallelic inactivation of B2M is frequently observed. We inactivated B2m in multiple murine MMRd cancer models. Although MMRd cells would not readily grow in immunocompetent mice, MMRd B2m null cells were tumorigenic and regressed when treated with anti-PD-1 and anti-CTLA4. The efficacy of ICPis against MMRd B2m null tumors did not require CD8(+) T cells but relied on the presence of CD4(+) T cells. Human tumors expressing low levels of B2M display increased intra-tumoral CD4(+) T cells. We conclude that B2M inactivation does not blunt the efficacy of ICPi in MMRd tumors, and we identify a unique role for CD4(+) T cells in tumor rejection.SIGNIFICANCE: B2M alterations, which impair antigen presentation, occur frequently in microsatellite-unstable colorectal cancers. Although in melanoma and lung cancers B2M loss is a mechanism of resistance to immune checkpoint blockade, we show that MMRd tumors respond to ICPis through CD4(+) T-cell activation.