Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy.
Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy.
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DOI：
10.1136/jitc-2022-005937
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发表时间：
2023-01
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
累积的数据表明，粘膜黑色素瘤，众所周知其对免疫检查点阻断（ICB）的反应差和预后差，是一种异质性黑色素瘤亚型，在原发性病变的不同解剖位置之间具有不同的基因组和临床特征。原发性食管恶性黑色素瘤（PMME）是一种罕见的高度侵袭性疾病，与非食管粘膜黑色素瘤（NEMM）相比预后较差。本研究回顾性分析了抗程序性死亡（PD）-1治疗PMME患者的疗效，并探讨其分子基础。回顾性分析PMME和NEMM患者在抗PD-1单药治疗下的缓解和生存情况。为了探讨PMME和NEMM之间治疗效果差异的分子机制，我们进行了基因组分析，批量RNA测序和多重免疫组织化学染色。我们发现PMME（n=28）对抗PD-1治疗的反应优于NEMM（n=64），客观反应率明显更高（33.3%（95% CI 14.3%至52.3%）vs 6.6%（95% CI 0.2%至12.9%））和疾病控制率（74.1%（95% CI 56.4%至91.7%）vs 37.7%（95% CI 25.2%至50.2%））。基因组测序分析显示，PMME的基因组畸变景观在经典癌症驱动基因中占主导地位，大约一半的PMME病例在BRAF，N/KRAS和NF 1中携带突变。相反，大多数NEMM病例是三重野生型。转录组分析显示，与NEMM相比，PMME显示出更显著的增殖和炎症特征，与抗原呈递和分化相关的基因表达更高，而免疫抑制特征更少，抑制性免疫检查点和去分化相关基因的表达更低。多重免疫组化分析也表明PMME中的CD 8 + T细胞浸润高于NEMM。PMME是粘膜黑色素瘤的异常值，显示恶性表型，但由于其独特的分子特征，对ICB的反应率特别高。根据解剖学来源对患者进行分层有助于在未来的前瞻性研究中验证我们的结果后对粘膜黑色素瘤患者进行临床决策。
Accumulating data suggest that mucosal melanoma, well known for its poor response to immune checkpoint blockade (ICB) and abysmal prognosis, is a heterogeneous subtype of melanoma with distinct genomic and clinical characteristics between different anatomic locations of the primary lesions. Primary malignant melanoma of the esophagus (PMME) is a rare, highly aggressive disease with a poorer prognosis compared with that of non-esophageal mucosal melanoma (NEMM). In this study, we retrospectively analyzed the efficacy of anti-programmed death (PD)-1 in patients with PMME and explored its molecular basis. The response and survival of patients with PMME and NEMM under anti-PD-1 monotherapy were retrospectively analyzed. To explore the molecular mechanisms of the difference in therapeutic efficacy between PMME and NEMM, we performed genomic analysis, bulk RNA sequencing, and multiplex immunohistochemistry staining. We found that PMME (n=28) responded better to anti-PD-1 treatment than NEMM (n=64), with a significantly higher objective response rate (33.3% (95% CI 14.3% to 52.3%) vs 6.6% (95% CI 0.2% to 12.9%)) and disease control rate (74.1% (95% CI 56.4% to 91.7%) vs 37.7% (95% CI 25.2% to 50.2%)). Genomic sequencing analysis revealed that the genomic aberration landscape of PMME predominated in classical cancer driver genes, with approximately half of PMME cases harboring mutations in BRAF, N/KRAS, and NF1. In contrast, most NEMM cases were triple wild-type. Transcriptome analysis revealed that, compared with NEMM, PMME displayed more significant proliferation and inflammatory features with higher expression of genes related to antigen presentation and differentiation, and a less immunosuppressive signature with lower expression of inhibitory immune checkpoints and dedifferentiation-related genes. The multiplex immunohistochemical analysis also demonstrated higher CD8+ T-cell infiltration in PMME than in NEMM. PMME is an outlier of mucosal melanoma showing a malicious phenotype but a particularly high response rate to ICB because of its distinct molecular characteristics. Patient stratification based on anatomic origin can facilitate clinical decision-making in patients with mucosal melanoma following the verification of our results in future prospective studies.
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DOI：
10.1016/j.omtn.2020.10.033
发表时间：
2021-03-05
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Chong W;Wang Z;Shang L;Jia S;Liu J;Fang Z;Du F;Wu H;Liu Y;Chen Y;Chen H
通讯作者：
Chen H
影响因子：
8.4
作者：
Kirchberger, Michael Constantin;Ugurel, Selma;Heinzerling, Lucie
通讯作者：
Heinzerling, Lucie
影响因子：
4.8
作者：
Kubic, Jennifer D.;Lui, Jason W.;Lang, Deborah
通讯作者：
Lang, Deborah
影响因子：
82.9
作者：
Gembarska, Agnieszka;Luciani, Flavie;Fedele, Clare;Russell, Elisabeth A.;Dewaele, Michael;Villar, Stephanie;Zwolinska, Aleksandra;Haupt, Sue;de Lange, Job;Yip, Dana;Goydos, James;Haigh, Jody J.;Haupt, Ygal;Larue, Lionel;Jochemsen, Aart;Shi, Hubing;Moriceau, Gatien;Lo, Roger S.;Ghanem, Ghanem;Shackleton, Mark;Bernal, Federico;Marine, Jean-Christophe
通讯作者：
Marine, Jean-Christophe
影响因子：
16.6
作者：
Adhikari H;Counter CM
通讯作者：
Counter CM