Clinical Significance of PDCD4 in Melanoma by Subcellular Expression and in Tumor-Associated Immune Cells.
Clinical Significance of PDCD4 in Melanoma by Subcellular Expression and in Tumor-Associated Immune Cells.
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DOI：
10.3390/cancers13051049
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发表时间：
2021-03-02
期刊：
影响因子：
5.2
通讯作者：
Jilaveanu LB
中科院分区：
文献类型：
--
作者：
Tran TT;Rane CK;Zito CR;Weiss SA;Jessel S;Lucca L;Lu BY;Oria VO;Adeniran A;Chiang VL;Omay SB;Hafler DA;Kluger HM;Jilaveanu LB
虽然靶向程序性细胞死亡（PDCD）1是针对黑色素瘤的中心治疗方法，但对相关蛋白PDCD 4知之甚少。我们定义了肿瘤发生过程中黑色素瘤PDCD4亚细胞定位（全细胞或仅核）的差异，评估了其在肿瘤浸润免疫细胞上的存在，并确定了其对生存的影响。PDCD4高表达可提高原发性和颅内转移性黑色素瘤患者的生存率，但对颅外转移性黑色素瘤患者无影响。周围肿瘤组织中的高PDCD4水平也与浸润性免疫细胞增加相关。PDCD4可能是黑色素瘤中潜在有用的生物标志物，有助于指导我们了解患者预后。在黑色素瘤脑转移患者中增加PDCD4的方法也可能有助于改善疾病反应。程序性细胞死亡4（PDCD4）在黑色素瘤中的亚细胞定位和功能知之甚少。我们过去的研究表明，PDCD4与含有A5的普列克底物蛋白同源结构域（PLEKHA5）相互作用，影响黑色素瘤脑转移的结果，因为颅内PDCD4高表达导致生存率提高。我们的目的是确定PDCD4在黑色素瘤中的亚细胞分布和肿瘤进展过程中的肿瘤微环境及其对临床结局的影响。我们使用定量免疫荧光分析了多个具有良好注释的临床病理变量的组织微阵列，并评估了脑转移样本的单细胞RNA测序，以表征PDCD4+免疫细胞亚群。我们证实了肿瘤进展过程中PDCD4表达的差异，高肿瘤和间质PDCD4水平与原发性黑色素瘤和颅内转移瘤的生存率提高相关，但与颅外转移性疾病无关。虽然PDCD 4的表达在CD 8 + T细胞和自然杀伤细胞上有充分的记录，但我们发现它也存在于B细胞和肥大细胞上。肿瘤微环境中的PDCD4表达与免疫细胞浸润增加相关。需要进一步的研究来确定PDCD4和PLEKHA5的相互作用，并评估该途径作为黑色素瘤脑转移治疗靶点的效用。
While targeting programmed cell death (PDCD) 1 is a central treatment against melanoma, little is known about the related protein PDCD4. We defined differences in melanoma PDCD4 subcellular localization (either total cellular or nuclear-only) during oncogenesis, evaluated its presence on tumor-infiltrating immune cells, and determined its impact on survival. High PDCD4 expression resulted in improved survival in patients with primary and intracranial but not extracranial metastatic melanoma. High PDCD4 levels in surrounding tumor tissue were also associated with increased infiltrating immune cells. PDCD4 may be a potentially useful biomarker in melanoma to help guide our understanding of patient prognosis. Methods to increase PDCD4 in those with melanoma brain metastases may also help improve disease response. Little is known about the subcellular localization and function of programmed cell death 4 (PDCD4) in melanoma. Our past studies suggest PDCD4 interacts with Pleckstrin Homology Domain Containing A5 (PLEKHA5) to influence melanoma brain metastasis outcomes, as high intracranial PDCD4 expression leads to improved survival. We aimed to define the subcellular distribution of PDCD4 in melanoma and in the tumor microenvironment during neoplastic progression and its impact on clinical outcomes. We analyzed multiple tissue microarrays with well-annotated clinicopathological variables using quantitative immunofluorescence and evaluated single-cell RNA-sequencing on a brain metastasis sample to characterize PDCD4+ immune cell subsets. We demonstrate differences in PDCD4 expression during neoplastic progression, with high tumor and stromal PDCD4 levels associated with improved survival in primary melanomas and in intracranial metastases, but not in extracranial metastatic disease. While the expression of PDCD4 is well-documented on CD8+ T cells and natural killer cells, we show that it is also found on B cells and mast cells. PDCD4 expression in the tumor microenvironment is associated with increased immune cell infiltration. Further studies are needed to define the interaction of PDCD4 and PLEKHA5 and to evaluate the utility of this pathway as a therapeutic target in melanoma brain metastasis.
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影响因子：
2.2
作者：
Graetz, Victoria;Langan, Ewan A.;Terheyden, Patrick
通讯作者：
Terheyden, Patrick
DOI：
10.1186/s13046-019-1069-3
发表时间：
2019-02-13
影响因子：
11.3
作者：
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影响因子：
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作者：
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影响因子：
5.3
作者：
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通讯作者：
Zhang L
影响因子：
56.9
作者：
Dorrello, N. Valerio;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele