Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement
Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement
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DOI：
10.1172/jci.insight.120360
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发表时间：
2018-12-20
期刊：
影响因子：
8
通讯作者：
Balko, Justin M.
中科院分区：
文献类型：
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作者：
Johnson, Douglas B.;Nixon, Mellissa J.;Balko, Justin M.
靶向PD-1通路的免疫疗法在许多癌症中产生持久的反应，但控制反应和耐药性的肿瘤内在因素在很大程度上是未知的。肿瘤细胞上的MHC-II表达可以预测对抗PD-1治疗的反应。因此，我们试图确定肿瘤细胞的MHC-II表达如何促进PD-1依赖性。使用抗PD-1治疗患者的转录谱分析，我们鉴定了MHC-II+肿瘤中免疫激活的独特模式。在患者和临床前模型中，MHC-II+肿瘤招募CD 4（+）T细胞，并对PD-1以及Lag-3（一种MHC-II抑制性受体）产生依赖性，Lag-3在MHC-II+肿瘤中对抗PD-1获得性耐药时上调。最后，我们鉴定了在MHC-II+肿瘤的微环境中，在NK和T细胞上表达的另一种MHC-II受体FCRL 6的增强表达。我们将其归因于我们认为是FCRL 6参与的一种新的抑制功能，将其确定为免疫治疗靶标。这些数据表明MHC-II介导的对PD-1靶向免疫疗法的适应性抗性的背景依赖性机制。
Immunotherapies targeting the PD-1 pathway produce durable responses in many cancers, but the tumor-intrinsic factors governing response and resistance are largely unknown. MHC-II expression on tumor cells can predict response to anti-PD-1 therapy. We therefore sought to determine how MHC-II expression by tumor cells promotes PD-1 dependency. Using transcriptional profiling of anti-PD-1-treated patients, we identified unique patterns of immune activation in MHC-II+ tumors. In patients and preclinical models, MHC-II+ tumors recruited CD4(+) T cells and developed dependency on PD-1 as well as Lag-3 (an MHC-II inhibitory receptor), which was upregulated in MHC-II+ tumors at acquired resistance to anti-PD-1. Finally, we identify enhanced expression of FCRL6, another MHC-II receptor expressed on NK and T cells, in the microenvironment of MHC-II+ tumors. We ascribe this to what we believe to be a novel inhibitory function of FCRL6 engagement, identifying it as an immunotherapy target. These data suggest a MHC-II-mediated context-dependent mechanism of adaptive resistance to PD-1-targeting immunotherapy.