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Abstract：
Skin melanoma cells are tightly interconnected with their tumor microenvironment (TME), which influences their initiation, progression, and sensitivity/resistance to therapeutic interventions. An immune-active TME favors patient response to immune checkpoint inhibition (ICI), but not all patients respond to therapy. Here, we assessed differential gene expression in primary and metastatic tumors from the TCGA-SKCM dataset, compared to normal skin samples from the GTEx project and validated key findings across 4 independent GEO datasets, as well as using immunohistochemistry in independent patient cohorts. We focused our attention on examining the expression of various immune receptors, immune-cell fractions, immune-related signatures and mutational signatures across cutaneous melanomas with diverse tumor mutation burdens (TMB). Globally, the expression of most immunoreceptors correlated with patient survival, but did not differ between TMBhigh and TMBlow tumors. Melanomas were enriched in \"naive T-cell\", \"effector memory T-cell\", \"exhausted T-cell\", \"resting Treg T-cell\" and \"Th1-like\" signatures, irrespective of their BRAF, NF1 or RAS mutational status. Somatic mutations in IDO1 and HLA-DRA were frequent and could be involved in hindering patient response to ICI therapies. We finally analyzed transcriptome profiles of ICI-treated patients and associated their response with high levels of IFNγ, Merck18, CD274, CD8, and low levels of myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs) and M2 macrophages, irrespective of their TMB status. Overall, our findings highlight the importance of pre-existing T-cell immunity in ICI therapeutic outcomes in skin melanoma and suggest that TMBlow patients could also benefit from such therapies.
摘要：
皮肤黑色素瘤细胞与它们的肿瘤微环境（TME）紧密相连，这影响了他们的开始，programming,和对治疗干预的敏感性/抗性。免疫活性TME有利于患者对免疫检查点抑制（ICI）的反应，但并非所有患者都对治疗有反应。这里,我们从TCGA-SKCM数据集评估了原发性和转移性肿瘤中的差异基因表达，与GTEx项目的正常皮肤样本进行比较，并验证了4个独立GEO数据集的关键发现，以及在独立患者队列中使用免疫组织化学。我们把注意力集中在检查各种免疫受体的表达上，免疫细胞部分，具有不同肿瘤突变负担（TMB）的皮肤黑色素瘤的免疫相关特征和突变特征。全球范围内,大多数免疫受体的表达与患者生存相关，但在TMBhigh和TMBlow肿瘤之间没有差异。黑色素瘤富含“幼稚T细胞”，“效应记忆T细胞”，“耗尽的T细胞”，“静息TregT细胞”和“Th1样”签名，不管他们的BRAF,NF1或RAS突变状态。IDO1和HLA-DRA中的体细胞突变很常见，可能与阻碍患者对ICI疗法的反应有关。我们最终分析了ICI治疗患者的转录组概况，并将他们的反应与高水平的IFNγ相关联，Merck18，CD274，CD8和低水平的骨髓衍生抑制细胞（MDSCs），癌症相关成纤维细胞（CAFs）和M2巨噬细胞，无论其TMB地位如何。总的来说,我们的研究结果强调了预先存在的T细胞免疫在皮肤黑色素瘤ICI治疗结局中的重要性,并提示TMBlow患者也可从此类治疗中获益.
