HHLA2 predicts improved prognosis of anti-PD-1/PD-L1 immunotherapy in patients with melanoma.
HHLA2 predicts improved prognosis of anti-PD-1/PD-L1 immunotherapy in patients with melanoma.
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DOI：
10.3389/fimmu.2022.902167
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作为公认的高免疫原性肿瘤，免疫检查点阻断（ICB）已被广泛用作黑色素瘤的全身治疗选择。然而，在白种人中只有大约一半的治疗患者可以从中受益，在中国黑色素瘤患者中只有大约15%。需要强有力的预测性生物标志物。HLA 2是B7家族的新成员，广泛表达于黑色素瘤等多种肿瘤中。本研究的重点是阐明HHLA 2在黑色素瘤免疫治疗中的预后价值及其与肿瘤浸润淋巴细胞的关系。通过选择生物信息学工具和方法分析TCGA数据库中的基因表达谱，确定HHLA 2在泛癌中的表达及其与预后和免疫微环境的相关性。采用免疫组织化学方法检测81例晚期不能手术切除的黑色素瘤组织中HHLA 2和CD 8的表达。HLA 2在全癌组织中广泛表达，且表达水平较高，与患者的预后相关。TCGA数据库进一步综合分析表明，皮肤黑色素瘤（SKCM）中HHLA 2的高表达与SKCM的良好预后、各种免疫活性细胞的高浸润状态和免疫激活途径显著相关。此外，来自黑色素瘤患者的FFPE组织的免疫组织化学（IHC）分析显示，HHLA 2高表达与对ICB的反应改善密切相关，并表明无进展生存期（PFS）和总生存期（OS）较长。HHLA 2表达与CD8+ TIL密度呈正相关。我们的研究结果显示，HHLA 2的高表达在预测ICB的反应以及指示晚期和不可切除的黑色素瘤患者的PFS和OS改善方面具有重要价值，这表明HHLA 2可能作为黑色素瘤的共刺激配体，这使其成为免疫治疗的理想生物标志物。
As a recognized highly immunogenic tumor, immune checkpoint blockades (ICB) have been widely used as a systemic treatment option for melanoma. However, only about half of treated patients could benefit from it in Caucasians, and only about 15% in Chinese melanoma patients. Robust predictive biomarkers are needed. HHLA2, a new-found member of B7 family, is generally expressed in kinds of tumors, such as melanoma. This study focuses on illustrating the prognostic value of HHLA2 in melanoma immunotherapy and its association with tumor-infiltrating lymphocytes. HHLA2 expression in pan-cancer and the association with prognosis and immune microenvironment were identified by analyzing gene expression profiles from TCGA database with selected bioinformatics tools and methods. Tumor tissues from 81 cases with advanced and unresectable melanoma were collected for detecting HHLA2 and CD8 levels by immunohistochemistry. HHLA2 was found to be ubiquitously expressed in pan-cancer with high level and correlate with the prognosis of patients. Further comprehensive analysis from TCGA database demonstrated that the highly expressed HHLA2 was remarkably correlated with better prognosis, high infiltration status of various immune-active cells and immune activated pathways in skin cutaneous melanoma (SKCM). Moreover, immunohistochemistry (IHC) analyses of FFPE tissue from melanoma patients revealed that HHLA2 high expression was strongly related to improved response to ICB and indicated a longer progression-free survival (PFS) and overall survival (OS). Besides, HHLA2 expression was found to have a positive association with the density of CD8+ TILs. Our findings revealed that high expression of HHLA2 has important values in predicting the response to ICB and indicating improved PFS and OS in patients with advanced and unresectable melanoma, suggesting that HHLA2 may serve as a costimulatory ligand in melanoma, which renders it as an ideal biomarker for immunotherapy.