Immunological and clinical immunotherapy implications of NLRP3 mutations in melanoma.
Immunological and clinical immunotherapy implications of NLRP3 mutations in melanoma.
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NLRP3 突变对黑色素瘤的免疫学和临床免疫治疗影响
DOI：
10.18632/aging.203678
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发表时间：
2021-11-08
期刊：
影响因子：
--
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Wang Q;Lyu J;Zhang W;Shi F;Ren Y;Mao Q;Liu Y;Li Y;Wang S
最近的研究证明了 Nod 样受体蛋白 3 (NLRP3) 炎症小体在促进黑色素瘤进展中的作用。免疫检查点抑制剂（ICI）治疗显着延长了晚期黑色素瘤患者的生存结果。然而，NLRP3 突变对黑色素瘤的免疫学和免疫治疗影响尚不清楚。在此，我们利用 750 名黑色素瘤患者的公开基因组数据来探索 NLRP3 突变与免疫学和基因组特征的关联。此外，我们从 6 项已发表的研究中筛选了 336 名接受 ICI 药物治疗的晚期/转移性黑色素瘤患者，以分析与 NLRP3 突变相关的缓解率和生存结果。我们观察到，NLRP3 突变的患者具有显着较高的肿瘤突变负荷（P < 0.001）和新抗原负荷（P < 0.001）。此外，在该突变亚组中还观察到显着较低的肿瘤异质性（P = 0.048）和纯度（P = 0.022）。 NLRP3 突变患者的免疫反应细胞浸润增加，免疫抑制细胞富集减少，免疫反应相关回路显着富集。在 ICI 治疗的汇总队列中，NLRP3 突变与较高的缓解率 (P = 0.031) 和更好的生存结果 (P = 0.006) 相关。 NLRP3 突变被确定与突变负荷升高、有利的免疫浸润和更好的 ICI 疗效相关。我们的研究结果表明，NLRP3 突变可能作为评估黑色素瘤免疫治疗反应的潜在生物标志物。
Recent studies have demonstrated the role of Nod-like receptor protein 3 (NLRP3) inflammasome in promoting melanoma progression. Immune checkpoint inhibitors (ICI) treatment dramatically extended the survival outcomes for advanced melanoma patients. Nevertheless, immunologic and immunotherapy implications of NLRP3 mutations in melanoma were obscure. Herein, we utilized publicly genomic data of 750 melanoma patients to explore the association of NLRP3 mutations with immunologic and genomic features. In addition, we curated 336 advanced/metastatic melanoma patients treated with ICI agents from 6 published studies to analyze the response rate and survival outcome in relation to NLRP3 mutations. We observed that patients with NLRP3 mutations had a significantly higher tumor mutation burden (P < 0.001) and neoantigen burden (P < 0.001). Moreover, significantly lower tumor heterogeneity (P = 0.048) and purity (P = 0.022) were also observed in this mutated subgroup. Elevated infiltration of immune-response cells, decreased enrichment of immune-suppressive cells, and immune response-related circuits were markedly enriched in patients with NLRP3 mutations. In the pooled ICI-treated cohort, NLRP3 mutations were linked with the higher response rate (P = 0.031) and preferable survival outcome (P = 0.006). NLRP3 mutations were identified to associate with the elevated mutational burden, favorable immune infiltration, and preferable ICI efficacy. Findings derived from our study suggest that NLRP3 mutations may serve as a potential biomarker for evaluating melanoma immunotherapy response.
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肌联蛋白突变与实体瘤检查点阻断的反应相关
影响因子：
8
作者：
Jia, Qingzhu;Wang, Jun;Zhu, Bo
通讯作者：
Zhu, Bo
影响因子：
64.5
作者：
Riaz N;Havel JJ;Makarov V;Desrichard A;Urba WJ;Sims JS;Hodi FS;Martín-Algarra S;Mandal R;Sharfman WH;Bhatia S;Hwu WJ;Gajewski TF;Slingluff CL Jr;Chowell D;Kendall SM;Chang H;Shah R;Kuo F;Morris LGT;Sidhom JW;Schneck JP;Horak CE;Weinhold N;Chan TA
通讯作者：
Chan TA
DOI：
10.1038/s41573-019-0041-4
发表时间：
2019-10
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Ferreira LMR;Muller YD;Bluestone JA;Tang Q
通讯作者：
Tang Q
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS
DOI：
10.1126/science.aar4060
发表时间：
2018-03-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ribas A;Wolchok JD
通讯作者：
Wolchok JD