Blockade of Tumor-Expressed PD-1 promotes lung cancer growth.
Blockade of Tumor-Expressed PD-1 promotes lung cancer growth.
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DOI：
10.1080/2162402x.2017.1408747
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Lu B
中科院分区：
文献类型：
--
作者：
Du S;McCall N;Park K;Guan Q;Fontina P;Ertel A;Zhan T;Dicker AP;Lu B
抗PD-1免疫治疗是许多非小细胞肺癌(NSCLC)患者的标准治疗方法，但治疗失败的机制正在出现。我们提出一个非小细胞肺癌的病例，在一项联合姑息性放射治疗和培布罗单抗的试验(NCT02318771)中进展迅速。计划的肿瘤活检显示非小细胞肺癌细胞表达PD-1。我们通过检测肺癌细胞中的PD-1转录本以及在切除的肺癌组织中共定位PD-1和肺癌特异性标记物来验证这一观察结果。我们进一步研究了肿瘤内源性PD-1在小鼠肺癌细胞系M109中的生物学作用。PD-1基因敲除或抗体阻断可提高M109细胞的体外存活率，而PD-1过表达和暴露于重组PD-L1可降低细胞存活率。PD-1阻断可加速M109-异种移植瘤的生长，促进免疫缺陷小鼠的增殖和减少细胞凋亡。这是首次报道非小细胞肺癌固有的PD-1表达，这是PD-1阻断可能促进肿瘤生长的潜在机制。
Anti-PD-1 immunotherapy is the standard of care for treating many patients with non-small cell lung cancer (NSCLC), yet mechanisms of treatment failure are emerging. We present a case of NSCLC, who rapidly progressed during a trial (NCT02318771) combining palliative radiotherapy and pembrolizumab. Planned tumor biopsy demonstrated PD-1 expression by NSCLC cells. We validated this observation by detecting PD-1 transcript in lung cancer cells and by co-localizing PD-1 and lung cancer-specific markers in resected lung cancer tissues. We further investigated the biological role of cancer-intrinsic PD-1 in a mouse lung cancer cell line, M109. Knockout or antibody blockade of PD-1 enhanced M109 viability in-vitro, while PD-1 overexpression and exposure to recombinant PD-L1 diminished viability. PD-1 blockade accelerated growth of M109-xenograft tumors with increased proliferation and decreased apoptosis in immune-deficient mice. This represents a first-time report of NSCLC-intrinsic PD-1 expression and a potential mechanism by which PD-1 blockade may promote cancer growth.