Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
J Immunother Cancer. 2020 Dec;8(2). doi: 10.1136/jitc-2020-001501.
BACKGROUND: The profound disparity in response to immune checkpoint blockade (ICB) by cutaneous melanoma (CM) and uveal melanoma (UM) patients is not well understood. Therefore, we characterized metastases of CM and UM from the same metastatic site (liver), in order to dissect the potential underlying mechanism in differential response on ICB. METHODS: Tumor liver samples from CM (n=38) and UM (n=28) patients were analyzed at the genomic (whole exome sequencing), transcriptional (RNA sequencing) and protein (immunohistochemistry and GeoMx Digital Spatial Profiling) level. RESULTS: Comparison of CM and UM metastases from the same metastatic site revealed that, although originating from the same melanocyte lineage, CM and UM differed in somatic mutation profile, copy number profile, tumor mutational burden (TMB) and consequently predicted neoantigens. A higher melanin content and higher expression of the melanoma differentiation antigen MelanA was observed in liver metastases of UM patients. No difference in B2M and human leukocyte antigen-DR (HLA-DR) expression was observed. A higher expression of programmed cell death ligand 1 (PD-L1) was found in CM compared with UM liver metastases, although the majority of CM and UM liver metastases lacked PD-L1 expression. There was no difference in the extent of immune infiltration observed between CM and UM metastases, with the exception of a higher expression of CD163 (p<0.0001) in CM liver samples. While the extent of immune infiltration was similar for CM and UM metastases, the ratio of exhausted CD8 T cells to cytotoxic T cells, to total CD8 T cells and to Th1 cells, was significantly higher in UM metastases. CONCLUSIONS: While TMB was different between CM and UM metastases, tumor immune infiltration was similar. The greater dependency on PD-L1 as an immune checkpoint in CM and the identification of higher exhaustion ratios in UM may both serve as explanations for the difference in response to ICB. Consequently, in order to improve current treatment for metastatic UM, reversal of T cell exhaustion beyond programmed cell death 1 blockade should be considered.
背景：皮肤黑色素瘤（CM）和葡萄膜黑色素瘤（UM）患者对免疫检查点阻断（ICB）的反应存在显著差异，但目前尚不清楚其原因。因此，我们对来自同一转移部位（肝脏）的 CM 和 UM 转移灶进行了特征分析，以深入了解导致这两种肿瘤对 ICB 反应存在差异的潜在机制。
方法：对来自 CM（n=38）和 UM（n=28）患者的肝脏肿瘤样本进行了基因组（全外显子测序）、转录组（RNA 测序）和蛋白质（免疫组化和 GeoMx 数字空间分析）水平的分析。
结果：对来自同一转移部位的 CM 和 UM 转移灶进行比较发现，尽管它们起源于同一黑色素细胞系，但 CM 和 UM 在体细胞突变谱、拷贝数谱、肿瘤突变负荷（TMB）和由此预测的新抗原方面存在差异。UM 患者的肝脏转移灶中黑色素含量较高，黑色素分化抗原 MelanA 的表达也较高。B2M 和人类白细胞抗原-DR（HLA-DR）的表达无差异。CM 肝脏转移灶中程序性细胞死亡配体 1（PD-L1）的表达高于 UM，但大多数 CM 和 UM 肝脏转移灶缺乏 PD-L1 表达。CM 和 UM 转移灶之间的免疫浸润程度无差异，但 CM 肝脏样本中 CD163 的表达更高（p<0.0001）。尽管 CM 和 UM 转移灶的免疫浸润程度相似，但耗尽的 CD8 T 细胞与细胞毒性 T 细胞、总 CD8 T 细胞和 Th1 细胞的比值在 UM 转移灶中显著更高。
结论：虽然 CM 和 UM 转移灶的 TMB 存在差异，但肿瘤免疫浸润程度相似。CM 对 PD-L1 作为免疫检查点的依赖性更高，以及在 UM 中观察到更高的衰竭比值，这两者都可能是导致它们对 ICB 反应不同的原因。因此，为了提高转移性 UM 的现有治疗效果，除了阻断程序性细胞死亡 1 之外，还应考虑逆转 T 细胞衰竭。
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