Adams Anngela C, Borden Elizabeth S, Macy Anne M, Thomson Nick, Cui Haiyan, Gimbel Mark I, Wilson Melissa A, Buetow Kenneth H, Roe Denise J, DiCaudo David J, Homsi Jade, Hastings Karen Taraszka
College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA.
Phoenix Veterans Affairs Health Care System, Phoenix, AZ 85012, USA.
Cancers (Basel). 2022 Apr 28;14(9):2200. doi: 10.3390/cancers14092200.
Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II restricted presentation of multiple melanoma antigens. There is variable GILT protein expression in malignant melanocytes in melanoma specimens. High GILT mRNA expression in melanoma specimens is associated with improved overall survival, before the advent of immune checkpoint inhibitors (ICI). However, the association of GILT in metastatic melanoma with survival in patients treated with ICI and the cell type expressing GILT associated with survival have not been determined. Using RNA sequencing datasets, high GILT mRNA expression in metastatic melanoma specimens was associated with improved progression-free and overall survival in patients treated with ICI. A clinical dataset of metastatic melanoma specimens was generated and annotated with clinical information. Positive GILT immunohistochemical staining in antigen presenting cells and melanoma cells was observed in 100% and 65% of metastatic melanoma specimens, respectively. In the subset of patients treated with ICI in the clinical dataset, high GILT protein expression within melanoma cells was associated with improved overall survival. The association of GILT mRNA and protein expression with survival was independent of cancer stage. These studies support that high GILT mRNA expression in bulk tumor samples and high GILT protein expression in melanoma cells is associated with improved survival in ICI-treated patients. These findings support further investigation of GILT as a biomarker to predict the response to ICI.
γ干扰素诱导的溶酶体硫醇还原酶（GILT）对于多种黑色素瘤抗原的MHC II类限制性呈递至关重要。黑色素瘤标本中的恶性黑色素细胞中GILT蛋白表达存在差异。在免疫检查点抑制剂（ICI）出现之前，黑色素瘤标本中高GILT mRNA表达与总体生存率提高相关。然而，转移性黑色素瘤中GILT与接受ICI治疗患者的生存率之间的关联以及与生存相关的表达GILT的细胞类型尚未确定。利用RNA测序数据集，转移性黑色素瘤标本中高GILT mRNA表达与接受ICI治疗患者的无进展生存期和总体生存率提高相关。生成了转移性黑色素瘤标本的临床数据集并用临床信息进行注释。在100%和65%的转移性黑色素瘤标本中，分别在抗原呈递细胞和黑色素瘤细胞中观察到GILT免疫组化染色阳性。在临床数据集中接受ICI治疗的患者亚组中，黑色素瘤细胞内高GILT蛋白表达与总体生存率提高相关。GILT mRNA和蛋白表达与生存的关联独立于癌症分期。这些研究支持，大块肿瘤样本中高GILT mRNA表达和黑色素瘤细胞中高GILT蛋白表达与接受ICI治疗患者的生存率提高相关。这些发现支持进一步研究将GILT作为预测对ICI反应的生物标志物。
