Fischer Sarah, Hamed Mohamed, Emmert Steffen, Wolkenhauer Olaf, Fuellen Georg, Thiem Alexander
Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany.
Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany.
Front Oncol. 2022 Jan 31;12:810058. doi: 10.3389/fonc.2022.810058. eCollection 2022.
Assessment of immune-specific markers is a well-established approach for predicting the response to immune checkpoint inhibitors (ICIs). Promising candidates as ICI predictive biomarkers are the DNA damage response pathway genes. One of those pathways, which are mainly responsible for the repair of DNA damage caused by ultraviolet radiation, is the nucleotide excision repair (NER) pathway. Xeroderma pigmentosum (XP) is a hereditary disease caused by mutations of eight different genes of the NER pathway, or POLH, here together named the nine XP genes. Anecdotal evidence indicated that XP patients with melanoma or other skin tumors responded impressively well to anti-PD-1 ICIs. Hence, we analyzed the expression of the nine XP genes as prognostic and anti-PD-1 ICI predictive biomarkers in melanoma.
We assessed mRNA gene expression in the TCGA-SKCM dataset (n = 445) and two pooled clinical melanoma cohorts of anti-PD-1 ICI (n = 75). In TCGA-SKCM, we applied hierarchical clustering on XP genes to reveal clusters, further utilized as XP cluster scores. In addition, out of 18 predefined genes representative of a T cell inflamed tumor microenvironment, the TIS score was calculated. Besides these scores, the XP genes, immune-specific single genes (CD8A, CXCL9, CD274, and CXCL13) and tumor mutational burden (TMB) were cross-correlated. Survival analysis in TCGA-SKCM was conducted for the selected parameters. Lastly, the XP response prediction value was calculated for the two pooled anti-PD-1 cohorts by classification models.
In TCGA-SKCM, expression of the XP genes was divided into two clusters, inversely correlated with immune-specific markers. A higher ERCC3 expression was associated with improved survival, particularly in younger patients. The constructed models utilizing XP genes, and the XP cluster scores outperformed the immune-specific gene-based models in predicting response to anti-PD-1 ICI in the pooled clinical cohorts. However, the best prediction was achieved by combining the immune-specific gene CD274 with three XP genes from both clusters.
Our results suggest pre-therapeutic XP gene expression as a potential marker to improve the prediction of anti-PD-1 response in melanoma.
评估免疫特异性标志物是预测免疫检查点抑制剂（ICI）疗效的一种成熟方法。作为ICI预测生物标志物的有前景的候选者是DNA损伤反应途径基因。其中一条主要负责修复紫外线辐射引起的DNA损伤的途径是核苷酸切除修复（NER）途径。着色性干皮病（XP）是一种由NER途径的八个不同基因或POLH（此处统称为九个XP基因）突变引起的遗传性疾病。轶事证据表明，患有黑色素瘤或其他皮肤肿瘤的XP患者对抗PD-1 ICI的反应非常好。因此，我们分析了九个XP基因的表达，作为黑色素瘤的预后和抗PD-1 ICI预测生物标志物。
我们评估了TCGA-SKCM数据集（n = 445）和两个抗PD-1 ICI临床黑色素瘤合并队列（n = 75）中的mRNA基因表达。在TCGA-SKCM中，我们对XP基因进行层次聚类以揭示簇，进一步用作XP簇评分。此外，在代表T细胞炎症肿瘤微环境的18个预定义基因中，计算TIS评分。除了这些评分外，还对XP基因、免疫特异性单基因（CD8A、CXCL9、CD274和CXCL13）和肿瘤突变负荷（TMB）进行了交叉关联分析。对TCGA-SKCM中选定的参数进行生存分析。最后，通过分类模型计算两个抗PD-1合并队列的XP反应预测值。
在TCGA-SKCM中，XP基因的表达分为两个簇，与免疫特异性标志物呈负相关。较高的ERCC3表达与改善的生存率相关，特别是在年轻患者中。在预测合并临床队列中对抗PD-1 ICI的反应时，利用XP基因构建的模型和XP簇评分优于基于免疫特异性基因的模型。然而，通过将免疫特异性基因CD274与来自两个簇的三个XP基因相结合，实现了最佳预测。
我们的结果表明，治疗前XP基因表达作为一种潜在标志物，可改善黑色素瘤中抗PD-1反应的预测。
