Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.

Significance: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer. Cancer Discov; 7(12); 1420–35. ©2017 AACR.

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对免疫检查点抑制剂（ICI）获得性耐药的机制了解甚少。我们利用14个对ICI有抗药性的肺癌样本的收集来研究编码HLA I类抗原加工和呈递机制（APM）组件或干扰素信号传导的基因的改变是否在获得性抗PD-1或PD-L1拮抗抗体中起作用。在我们的队列中未检测到复发性突变或拷贝数变化。在一个案例中，我们发现获得性的B2M纯合性缺失导致肿瘤中缺乏细胞表面HLA I类表达，并且没有匹配的患者来源的异种移植物（PDX）。从ICI耐药性肿瘤建立的另外两个PDX中也发现了B2M的下调。CRISPR介导的B2m基因敲除在具有免疫能力的肺癌小鼠模型中，在体内赋予了对PD-1阻断的抗性，证明了其在对ICI的抗性中的作用。这些结果表明，HLA I类APM破坏可以介导肺癌中ICI的逃逸。

意义：随着程序性死亡1轴抑制剂在用于各种恶性肿瘤的标准治疗算法中变得越来越成熟，对这些疗法的获得性耐药性也越来越多。在这里，我们发现有缺陷的抗原加工和呈递可以作为肺癌中这种耐药性的机制。巨蟹座Discov; 7（12）；1420–35。©2017 AACR。

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