Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma
Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma
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DOI：
10.1136/jitc-2019-000319
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Zhang, Tian
中科院分区：
文献类型：
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作者：
Labriola, Matthew Kyle;Zhu, Jason;Zhang, Tian
免疫检查点抑制剂（ICIs）扩大了转移性肾细胞癌（mRCC）的治疗选择；然而，在这一适应症中，对ICIs反应的预测性生物标志物有限，程序性死亡配体1 （PD-L1）状态在mRCC中显示出很少的预测效用。虽然预测其他肿瘤类型的ICI反应，但肿瘤突变负荷（TMB）在mRCC中的应用尚不清楚。在这里，我们评估了TMB、抗原呈递基因缺失和PD-L1状态与mRCC中ICI治疗结果的相关性。方法回顾性分析来自杜克癌症研究所34例接受ICI治疗的mRCC患者的肿瘤样本，使用Personal Genome Diagnostics elio tissue complete （RUO版本），这是一种肿瘤基因组分析方法，用于检测体细胞变异、TMB、微卫星状态和抗原呈递基因的基因组状态。用Dako 28-8 PD-L1免疫组化法分析肿瘤样本。从病历中提取未识别的临床信息，并根据实体肿瘤反应评价标准（RECIST） V.1.1标准评估肿瘤反应。结果根据ICI治疗后的总体反应将患者分层，分为进展性疾病组（PD, n=18）和疾病对照组（DC, n=16）。TMB评分范围为0.36 ~ 12.24个突变/Mb（平均2.83个突变/Mb）， PD组和DC组之间无显著差异（分别为3.01 vs 2.63个突变/Mb， p=0.7682）。有趣的是，33%的PD患者表现出主要组织相容性复合体I类基因（LOH-MHC）的杂合性缺失，而DC患者的这一比例为6%。34例样本中有9例PD- l1阳性（PD组4例，DC组5例），提示PD- l1表达与ICI治疗反应无相关性。值得注意的是，DC组DNA修复基因突变丰富（p=0.04）， 68.8%的患者至少有一个同源重组修复（HRR）相关基因突变，而PD组只有38.9% （p=0.03）。结论总体而言，TMB和PD-L1与ICI反应均无相关性，TMB与PD-L1表达无显著相关性。PD组较高的LOH-MHC发生率提示抗原呈递缺失可能限制了对ICIs的反应。另外，DC组中HRR基因突变的富集表明，在预测ICI反应和潜在治疗靶点方面具有潜在的实用性，值得未来的研究。
BackgroundImmune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand 1 (PD-L1) status demonstrating little predictive utility in mRCC. While predictive of ICI response in other tumor types, the utility of tumor mutation burden (TMB) in mRCC is unclear. Here, we assess TMB, loss of antigen presentation genes and PD-L1 status correlated with outcomes to ICI treatment in mRCC.MethodsTumor samples from 34 patients with mRCC treated with ICI therapy at Duke Cancer Institute were retrospectively evaluated using Personal Genome Diagnostics elio tissue complete (RUO version), a tumor genomic profiling assay for somatic variants, TMB, microsatellite status and genomic status of antigen presentation genes. Tumor samples were also analyzed with the Dako 28-8 PD-L1 immunohistochemistry assay. Deidentified clinical information was extracted from the medical record, and tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1 criteria.ResultsPatients were stratified by overall response following ICI therapy and designated as progressive disease (PD; n=18) or disease control groups (DC; n=16). TMB scores ranged from 0.36 to 12.24 mutations/Mb (mean 2.83 mutations/Mb) with no significant difference between the PD and DC groups (3.01 vs 2.63 mutations/Mb, respectively; p=0.7682). Interestingly, 33% of PD patients displayed loss of heterozygosity of major histocompatibility complex class I genes (LOH-MHC) vs 6% of DC patients. Nine of 34 samples were PD-L1-positive (4 in the PD group; 5 in the DC group), suggesting no correlation between PD-L1 expression and response to ICI therapy. Notably, the DC group displayed an enrichment of mutations in DNA repair genes (p=0.04), with 68.8% exhibiting at least one mutated homologous recombination repair (HRR)-related gene compared with only 38.9% of the PD group (p=0.03).ConclusionsOverall, neither TMB nor PD-L1 correlated with ICI response and TMB was not significantly associated with PD-L1 expression. The higher incidence of LOH-MHC in PD group suggests that loss of antigen presentation may restrict response to ICIs. Separately, enrichment of HRR gene mutations in the DC group suggests potential utility in predicting ICI response and a potential therapeutic target, warranting future studies.