Skin proteomic analysis of immune activation associated with regression of melanoma metastases induced by diphencyprone.
Skin proteomic analysis of immune activation associated with regression of melanoma metastases induced by diphencyprone.
复制标题
皮肤蛋白质组学分析的免疫激活与辅助链酮诱导的黑色素瘤转移的消退有关。
DOI：
10.1016/j.jdin.2022.08.006
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发表时间：
2022-12
影响因子：
--
通讯作者：
Gulati, Nicholas
中科院分区：
文献类型：
--
作者：
Han, Joseph;da Rosa, Joel Correa;Owji, Shayan;Yassky, Daniel;Lu, Yen;Estrada, Yeriel;Ungar, Jonathan;Ji, Andrew;Krueger, James G.;Gulati, Nicholas
关键词：
编者按：敌苯环酮(DPCP)是一种会导致迟发性超敏反应的半抗原，已被用于治疗黑色素瘤患者的疣、斑秃和皮肤转移。1此前，我们小组对局部应用DPCP治疗的黑色素瘤转移瘤的皮肤活检组织进行了转录转录分析，发现Th1相关基因显著增加，但其他主要T细胞亚群的基因没有显著增加。2虽然基因表达谱长期以来一直被用作蛋白质表达的替代指标，但由于转录后调控等因素，信使RNA(MRNA)和蛋白质水平之间的相关性并不一致。因此，为了更准确地确定DPCP诱导的免疫介导的肿瘤消退的机制，我们对5名接受DPCP治疗的皮肤黑色素瘤转移患者的皮肤活检进行了蛋白质组学分析，每周两次，持续7至14周(补充材料和方法以及补充表I，可从https://doi.的Mendeley获得Org/10.17632/f5ttw4mygy。1)。在这项研究中，我们使用Olink免疫肿瘤学小组对5名接受分子侧写的患者的96种蛋白质进行了评估。所有患者都预期皮肤炎症和至少部分皮肤转移消退，没有全身副作用。有10种蛋白(IL-6、IL-12、IL-18、TIE2、HGF、PDGFB、TNFSF14、PD-L2、MMP7、MMP12)显著上调(P<；05)在治疗后和治疗前转移(图1)，包括与Th1反应(IL-12)、天然免疫(IL-6)和免疫检查点(PD-L2)相关的生物标记物(P<；05)。在反复应用DPCP的皮肤转移瘤中，所有这些蛋白的表达都逐渐增加，在单次应用DPCP后，这些患者的非皮损皮肤中也观察到类似的增加。先前的工作已经表明，在小鼠中给予IL-18可以增加激活的T细胞和自然杀伤细胞，这有助于有效的抗黑色素瘤免疫，3所以我们研究中这种蛋白的显著上调可能有助于在我们的患者中观察到成功的皮肤转移消退。TNFSF14也可能在免疫介导的消退中发挥积极作用，因为体内研究表明该蛋白在黑色素瘤转移灶中的表达与T细胞的增殖之间存在关联。4此外，与未经治疗的非皮损皮肤相比，有40种蛋白质在治疗前转移的皮肤中显著上调(P<；。05)(图1)，提示黑色素瘤转移的基线免疫激活。在DPCP治疗后，非皮损皮肤的变化与皮肤转移的变化呈正相关(补充图1，可从https://doi.的门德利获得Org/10.17632/f5ttw4mygy。1；Spearman相关系数=0.61，P<；0001)。
To the Editor: Diphencyprone (DPCP), a hapten that causes delayed-type hypersensitivity reactions, has been used to treat warts, alopecia areata, and cutaneous metastases in melanoma patients. 1 Previously, our group performed transcriptomic analysis of skin biopsies from melanoma metastases treated with topical DPCP, revealing significant increases in Th1-related genes but not in genes of other major T-cell subsets. 2 While gene expression profiling has long been used as a proxy for protein expression, correlation between messenger RNA (mRNA) and protein levels is inconsistent due to factors such as post-transcriptional regulation. Therefore, to more precisely ascertain the mechanisms involved in immune-mediated tumor regression induced by DPCP, we performed proteomic analysis of skin biopsies from 5 patients with cutaneous melanoma metastases treated with DPCP twice weekly for 7 to 14 weeks (Supplemental Material and Methods and Supplementary Table I, available via Mendeley at https://doi. org/10.17632/f5ttw4mygy. 1). In this study, we assessed 96 proteins using the Olink immuno-oncology panel for the 5 patients who underwent molecular profiling.All patients had expected skin inflammation and at least partial regression of skin metastases, without systemic side effects. There were 10 proteins (interleukin 6 [IL-6], IL-12, IL-18, TIE2, HGF, PDGFB, TNFSF14, PD-L2, MMP7, MMP12) significantly upregulated (P<. 05) in post-treatment versus pretreatment metastases (Fig 1), including biomarkers associated with Th1 response (IL-12), innate immunity (IL-6), and immune checkpoints (PD-L2)(P<. 05). All of these proteins had progressively increased expression in cutaneous metastases with repeated DPCP applications, and similar increases were observed in nonlesional skin of these patients following a single DPCP application. Prior work has shown that administration of IL-18 in mice increases activated T cells and natural killer cells that contribute to effective antimelanoma immunity, 3 so the significant upregulation of this protein in our study may contribute to the successful skin metastasis regression observed in our patients. TNFSF14 also likely plays an active role in immune-mediated regression, as in vivo studies have demonstrated an association between the expression of this protein in melanoma metastasis lesions and proliferation of T cells. 4 Additionally, there were 40 proteins significantly upregulated in pretreatment metastases versus untreated nonlesional skin (P<. 05)(Fig 1), suggesting baseline immune activation in melanoma metastases. Upon DPCP treatment, changes in nonlesional skin positively correlated with those in skin metastases (Supplementary Fig 1, available via Mendeley at https://doi. org/10.17632/f5ttw4mygy. 1; Spearman correlation= 0.61, P<. 0001).
DOI：
10.1073/pnas.1908052116
发表时间：
2019-11-26
影响因子：
11.1
作者：
Mauger, David M.;Cabral, B. Joseph;McFadyen, Iain J.
通讯作者：
McFadyen, Iain J.
影响因子：
64.8
作者：
Zhou, Ting;Damsky, William;Ring, Aaron M.
通讯作者：
Ring, Aaron M.
影响因子：
11.2
作者：
Mortarini, R;Scarito, A;Anichini, A
通讯作者：
Anichini, A