High GILT Expression Is Associated with Improved Survival in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition.
High GILT Expression Is Associated with Improved Survival in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition.
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DOI：
10.3390/cancers14092200
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发表时间：
2022-04-28
期刊：
影响因子：
5.2
通讯作者：
Hastings, Karen Taraszka
中科院分区：
文献类型：
--
作者：
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
皮肤癌是最常见的癌症类型，黑色素瘤由于其转移倾向而成为最致命的皮肤癌之一。免疫检查点抑制剂（ICI）产生抗肿瘤免疫反应，从而改善转移性黑色素瘤患者的预后。然而，只有一小部分黑色素瘤患者对这些疗法有反应，这些疗法成本高昂，并且存在不良反应的风险。因此，需要生物标志物来预测哪些患者会对 ICI 产生反应。我们发现，接受 ICI 治疗的转移性黑色素瘤患者在肿瘤样本中具有高 GILT mRNA 表达，其生存率有所提高。此外，转移性黑色素瘤细胞内高 GILT 蛋白表达与 ICI 治疗患者生存率的改善相关。这项研究表明，GILT 可以作为预测哪些患者会对 ICI 做出反应的生物标志物，这可以改善患者护理，降低医疗成本，并有助于为转移性黑色素瘤患者选择适当的治疗方法。 γ-干扰素诱导的溶酶体硫醇还原酶 (GILT) 对于 MHC II 类限制性多种黑色素瘤抗原的呈递至关重要。黑色素瘤标本中的恶性黑色素细胞中存在可变的 GILT 蛋白表达。在免疫检查点抑制剂 (ICI) 出现之前，黑色素瘤标本中高 GILT mRNA 表达与总体生存率的提高相关。然而，转移性黑色素瘤中的 GILT 与 ICI 治疗患者的生存率之间的关系以及表达 GILT 与生存率相关的细胞类型尚未确定。使用 RNA 测序数据集发现，转移性黑色素瘤标本中高 GILT mRNA 表达与接受 ICI 治疗的患者无进展生存期和总生存期的改善相关。生成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。分别在 100% 和 65% 的转移性黑色素瘤标本中观察到抗原呈递细胞和黑色素瘤细胞的 GILT 免疫组织化学染色呈阳性。在临床数据集中接受 ICI 治疗的患者子集中，黑色素瘤细胞内高 GILT 蛋白表达与总体生存率改善相关。 GILT mRNA 和蛋白表达与生存的关联与癌症分期无关。这些研究支持大量肿瘤样本中高 GILT mRNA 表达和黑色素瘤细胞中高 GILT 蛋白表达与 ICI 治疗患者生存率的改善相关。这些发现支持进一步研究 GILT 作为预测 ICI 反应的生物标志物。
Skin cancer is the most common type of cancer, with melanoma being among the deadliest of skin cancers due to its propensity to metastasize. Immune checkpoint inhibitors (ICI) generate anti-tumor immune responses resulting in improved outcomes in patients with metastatic melanoma. However, only a subset of melanoma patients responds to these therapies, which are costly and come with a risk of adverse effects. Therefore, there is a need for biomarkers to predict which patients will respond to ICI. We found that ICI-treated metastatic melanoma patients with high GILT mRNA expression in bulk tumor samples had improved survival. Additionally, high GILT protein expression within metastatic melanoma cells was associated with improved survival in patients treated with ICI. This study suggests that GILT may serve as a biomarker to predict which patients will respond to ICI, which could improve patient care, reduce healthcare costs, and facilitate appropriate selection of therapies for patients with metastatic melanoma. 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.
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DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
14.9
作者：
Howe KL;Achuthan P;Allen J;Allen J;Alvarez-Jarreta J;Amode MR;Armean IM;Azov AG;Bennett R;Bhai J;Billis K;Boddu S;Charkhchi M;Cummins C;Da Rin Fioretto L;Davidson C;Dodiya K;El Houdaigui B;Fatima R;Gall A;Garcia Giron C;Grego T;Guijarro-Clarke C;Haggerty L;Hemrom A;Hourlier T;Izuogu OG;Juettemann T;Kaikala V;Kay M;Lavidas I;Le T;Lemos D;Gonzalez Martinez J;Marugán JC;Maurel T;McMahon AC;Mohanan S;Moore B;Muffato M;Oheh DN;Paraschas D;Parker A;Parton A;Prosovetskaia I;Sakthivel MP;Salam AIA;Schmitt BM;Schuilenburg H;Sheppard D;Steed E;Szpak M;Szuba M;Taylor K;Thormann A;Threadgold G;Walts B;Winterbottom A;Chakiachvili M;Chaubal A;De Silva N;Flint B;Frankish A;Hunt SE;IIsley GR;Langridge N;Loveland JE;Martin FJ;Mudge JM;Morales J;Perry E;Ruffier M;Tate J;Thybert D;Trevanion SJ;Cunningham F;Yates AD;Zerbino DR;Flicek P
通讯作者：
Flicek P
影响因子：
4.4
作者：
Hastings, K. Taraszka;Lackman, Rebecca L.;Cresswell, Peter
通讯作者：
Cresswell, Peter
影响因子：
4.4
作者：
Deffrennes, V;Vedrenne, J;Alcaïde-Loridan, C
通讯作者：
Alcaïde-Loridan, C
影响因子：
16.6
作者：
Johnson DB;Estrada MV;Salgado R;Sanchez V;Doxie DB;Opalenik SR;Vilgelm AE;Feld E;Johnson AS;Greenplate AR;Sanders ME;Lovly CM;Frederick DT;Kelley MC;Richmond A;Irish JM;Shyr Y;Sullivan RJ;Puzanov I;Sosman JA;Balko JM
通讯作者：
Balko JM