The Intratumoral Balance between Metabolic and Immunologic Gene Expression Is Associated with Anti-PD-1 Response in Patients with Renal Cell Carcinoma.
The Intratumoral Balance between Metabolic and Immunologic Gene Expression Is Associated with Anti-PD-1 Response in Patients with Renal Cell Carcinoma.
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DOI：
10.1158/2326-6066.cir-16-0072
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发表时间：
2016-09-02
影响因子：
10.1
通讯作者：
Topalian SL
中科院分区：
文献类型：
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作者：
Ascierto ML;McMiller TL;Berger AE;Danilova L;Anders RA;Netto GJ;Xu H;Pritchard TS;Fan J;Cheadle C;Cope L;Drake CG;Pardoll DM;Taube JM;Topalian SL
治疗前肿瘤PD-L1表达与抗PD-1/PD-L1治疗的应答相关。然而，大多数PD-L1+肿瘤患者对治疗无反应。本研究旨在研究PD-1靶向治疗在肿瘤表达PD-L1的晚期肾细胞癌（RCC）患者中失败的潜在机制。福尔马林固定，石蜡包埋（FFPE）预处理肿瘤活检表达PD-L1来自13个RCC患者。从PD-L1+区域分离RNA，并进行全基因组微阵列和多重定量（q）RT-PCR基因表达分析。反映代谢途径和免疫功能的基因表达谱之间的平衡与抗PD-1治疗后的临床结局相关。特别是，参与代谢和溶质转运功能的基因（如UGT 1A家族成员，也在肾癌细胞系中发现）的表达与PD-L1+ RCC患者的治疗失败相关。相反，来自应答患者的肿瘤过表达免疫标记物，如BACH 2（CD 4 + T细胞分化的调节剂）和CCL 3（参与白细胞迁移）。这些发现表明，肿瘤细胞内在代谢因子可能导致RCC的治疗耐药性，因此可作为治疗结果的预测标志物和抗PD-1联合治疗方案的潜在新靶点。
Pretreatment tumor PD-L1 expression correlates with response to anti-PD-1/PD-L1 therapies. Yet, most patients with PD-L1+ tumors do not respond to treatment. The current study was undertaken to investigate mechanisms underlying the failure of PD-1–targeted therapies in patients with advanced renal cell carcinoma (RCC) whose tumors express PD-L1. Formalin-fixed, paraffin-embedded (FFPE) pretreatment tumor biopsies expressing PD-L1 were derived from 13 RCC patients. RNA was isolated from PD-L1+ regions and subjected to whole genome microarray and multiplex quantitative (q)RT-PCR gene expression analysis. A balance between gene expression profiles reflecting metabolic pathways and immune functions was associated with clinical outcomes following anti-PD-1 therapy. In particular, the expression of genes involved in metabolic and solute transport functions such as UGT1A family members, also found in kidney cancer cell lines, was associated with treatment failure in patients with PD-L1+ RCC. Conversely, tumors from responding patients overexpressed immune markers such as BACH2, a regulator of CD4+ T cell differentiation, and CCL3, involved in leukocyte migration. These findings suggest that tumor cell–intrinsic metabolic factors may contribute to treatment resistance in RCC, thus serving as predictive markers for treatment outcomes and potential new targets for combination therapy regimens with anti-PD-1.