CCND1 Amplification Profiling Identifies a Subtype of Melanoma Associated With Poor Survival and an Immunosuppressive Tumor Microenvironment.
CCND1 Amplification Profiling Identifies a Subtype of Melanoma Associated With Poor Survival and an Immunosuppressive Tumor Microenvironment.
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CCND1扩增分析鉴定了与存活不良和免疫抑制性肿瘤微环境相关的黑色素瘤亚型。
DOI：
10.3389/fimmu.2022.725679
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发表时间：
2022
影响因子：
7.3
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Liu J;Lin J;Wang X;Zheng X;Gao X;Huang Y;Chen G;Xiong J;Lan B;Chen C;Si L;Chen Y
虽然黑色素瘤通常被认为是一种免疫原性癌症，会对免疫检查点抑制剂（ICI）产生反应，但CCND 1扩增的黑色素瘤对这些疗法的反应很差。进一步了解CCND 1扩增如何影响ICI治疗的有效性对于未来临床试验的设计非常重要。我们使用来自在Geneplus研究所分析的中国黑色素瘤患者的肿瘤样本的数据（n=302），以及来自癌症基因组图谱（TCGA）数据库（n=367）和纪念斯隆-凯特琳癌症中心（MSKCC）数据库（n=350）的数据来估计黑色素瘤中CCND 1扩增的患病率，探讨CCND 1扩增与黑色素瘤患者生存率的关系，并探索CCND 1扩增的分子机制。我们还建立了一个携带CCND 1扩增的黑色素瘤小鼠模型，并利用RNA-seq验证了来自人类组织样本的发现。来自所有三个来源的数据显示，CCND 1扩增与BRAF V600、NRAS、NF 1和KIT突变共同发生的频率较低。来自TCGA的数据未显示CCND 1扩增与预后之间的统计学显著相关性，与ICI的使用无关。相比之下，MSKCC队列显示CCND 1扩增是黑色素瘤患者的不利预后因素，特别是对于接受ICI和具有高肿瘤突变负荷（TMB）的患者。TCGA数据显示，CCND 1扩增与较高比例的免疫抑制细胞（Treg细胞和M2巨噬细胞）和较低比例的免疫增强细胞（滤泡辅助T细胞幼稚B细胞，CD 8 + T细胞）相关。小鼠模型支持抑制性免疫微环境与CCND 1扩增之间的关联;具有CCND 1扩增的肿瘤具有CD 8、Gzm、B2 m和Tap 1的mRNA表达降低，静息CD 4记忆T细胞的比例显著较高，浆细胞、CD 8 T细胞和T滤泡辅助细胞的比例显著较低。此外，基因集富集分析（GSEA）的数据从TCGA数据库的分析表明，参与氧化磷酸化，活性氧，脂肪形成，脂肪酸代谢，DNA修复，和Myc靶点的信号转导途径在黑色素瘤肿瘤与CCND 1扩增差异富集。最后，我们观察到在TCGA数据库的CCND 1高扩增组中血管生成相关分子（由HIF 1A、VEGFA、VEGFR 1、FGF 2、FGFR 1、FGFR 4、HGF、PDGFA、PDGFRA、ANGPT 1和ANGPT 2编码）的水平显著降低。具有CCND 1扩增的黑素瘤是与不良预后、免疫抑制性TME、活化的氧化和脂质代谢以及下调的血管生成相关的独立基因组亚型。因此，避免ICI和抗血管生成剂，同时单独使用CDK 4/6抑制剂或与ICI联合使用，并靶向氧化和脂质代谢途径，可能是携带CCND 1扩增的黑色素瘤患者的有效治疗策略。
Although melanoma is generally regarded as an immunogenic cancer that will respond to immune checkpoint inhibitors (ICIs), melanomas with CCND1 amplification respond poorly to these therapies. Further understanding how CCND1 amplification impacts the effectiveness of ICI therapy is important for the design of future clinical trials. We used data from tumor samples taken from Chinese patients with melanoma analyzed at the Geneplus Institute (n=302), as well as data from the Cancer Genome Atlas (TCGA) database (n=367) and the Memorial Sloan Kettering Cancer Center (MSKCC) database (n=350) to estimate the prevalence of CCND1 amplification in melanoma, interrogate the relationship between CCND1 amplification and survival in patients with melanoma, and explore the molecular mechanisms of CCND1 amplification. We also established a murine model of melanoma harboring CCND1 amplification and utilized RNA-seq to verify the findings from human tissue samples. Data from all three sources revealed a low frequency of CCND1 amplification co-occurring with BRAF V600, NRAS, NF1, and KIT mutations. Data from TCGA did not show a statistically significant correlation between CCND1 amplification and prognosis, irrespective of ICI use. In contrast, the MSKCC cohort showed that CCND1 amplification was an unfavorable prognostic factor for patients with melanoma, especially for patients who received ICIs and had a high tumor mutation burden (TMB). The TCGA data showed that CCND1 amplification was associated with a higher proportion of immunosuppressive cells (Treg cells and M2 macrophages) and a lower proportion of immune boosting cells (follicular helper T cells naïve B cells, CD8+ T cells). Murine models supported the association between a suppressive immune microenvironment and CCND1 amplification; tumors with CCND1 amplification had reduced mRNA expression of CD8, Gzm, B2m and Tap1, significantly higher proportions of resting CD4 memory T cells and significantly lower proportions of plasma cells, CD8 T cells, and T follicular helper cells. Furthermore, a Gene Set Enrichment Analysis (GSEA) analysis of data from the TCGA database suggested that signaling pathways involved in oxidative phosphorylation, reactive oxygen species, adipogenesis, fatty acid metabolism, DNA repair, and Myc targets were differentially enriched in melanoma tumors with CCND1 amplification. Finally, we observed a notable reduction in levels of angiogenesis-related molecules (encoded by HIF1A, VEGFA, VEGFR1, FGF2, FGFR1, FGFR4, HGF, PDGFA, PDGFRA, ANGPT1, and ANGPT2) in a high CCND1 amplification group from the TCGA database. Melanoma with CCND1 amplification is an independent genomic subtype associated with a poor prognosis, an immunosuppressive TME, activated oxidative and lipid metabolism, and down-regulated angiogenesis. Therefore, avoiding ICIs and antiangiogenic agents, while employing CDK4/6 inhibitors alone or in combination with ICIs, and targeting oxidative and lipid metabolism pathways, may be effective therapeutic strategies for melanoma patients harboring CCND1 amplification.
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影响因子：
11.1
作者：
Ascierto, Paolo A.;Marincola, Francesco M.
通讯作者：
Marincola, Francesco M.
影响因子：
3.8
作者：
Chi Z;Li S;Sheng X;Si L;Cui C;Han M;Guo J
通讯作者：
Guo J
影响因子：
51.1
作者：
Dummer, Reinhard;Schadendorf, Dirk;Flaherty, Keith
通讯作者：
Flaherty, Keith
DOI：
10.1126/science.aar3593
发表时间：
2018-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cristescu R;Mogg R;Ayers M;Albright A;Murphy E;Yearley J;Sher X;Liu XQ;Lu H;Nebozhyn M;Zhang C;Lunceford JK;Joe A;Cheng J;Webber AL;Ibrahim N;Plimack ER;Ott PA;Seiwert TY;Ribas A;McClanahan TK;Tomassini JE;Loboda A;Kaufman D
通讯作者：
Kaufman D
DOI：
10.1126/science.1229259
发表时间：
2013-02-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Huang FW;Hodis E;Xu MJ;Kryukov GV;Chin L;Garraway LA
通讯作者：
Garraway LA