Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy.
Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy.
复制标题
PD-1，PD-1配体的关联以及肿瘤免疫微环境的其他特征与抗PD-1治疗的响应。
DOI：
10.1158/1078-0432.ccr-13-3271
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发表时间：
2014-10-01
期刊：
影响因子：
--
通讯作者：
Anders RA
中科院分区：
文献类型：
--
作者：
Taube JM;Klein A;Brahmer JR;Xu H;Pan X;Kim JH;Chen L;Pardoll DM;Topalian SL;Anders RA
免疫调节药物的作用机制与直接细胞毒性癌症疗法不同。识别预测临床反应的因素可以指导患者选择和治疗优化。患有黑色素瘤、非小细胞肺癌（NSCLC）、肾细胞癌（RCC）、结直肠癌或去势抵抗性前列腺癌的患者（N=41）在一个机构的抗PD-1（纳武单抗）的早期试验中接受治疗，并且具有可评价的治疗前肿瘤标本。评估了免疫结构特征（包括PD-1、PD-L1和PD-L2表达、免疫细胞浸润模式和淋巴细胞亚群）与临床结局的相互关系和潜在相关性。肿瘤细胞和免疫浸润的膜（细胞表面）PD-L1表达因肿瘤类型而异，在黑色素瘤、NSCLC和RCC中最丰富。在整个队列中，PD-L1表达在地理上与浸润性免疫细胞相关（p<0.001），尽管富含淋巴细胞的区域并不总是与PD-L1表达相关。肿瘤细胞和免疫浸润的PD-L1表达与淋巴细胞上的PD-1表达显著相关。PD-1的第二配体PD-L2与PD-L1表达相关。当分析最接近治疗的标本或个体患者多次活检中评分最高的样本时，肿瘤细胞PD-L1表达与抗PD-1治疗的客观缓解相关。这些相关性强于PD-1表达或肿瘤内免疫细胞浸润与反应的边界相关性。肿瘤PD-L1表达反映了免疫活性微环境，而与其他免疫抑制分子（包括PD-1和PD-L2）相关，是与抗PD-1阻断反应最密切相关的单一因素。
Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. Patients (N=41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma or castration-resistant prostate cancer were treated on an early phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pre-treatment tumor specimens. Immunoarchitectural features including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (p<0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade.