Spatial Immunoprofiling of Adenoid Cystic Carcinoma Reveals B7-H4 Is a Therapeutic Target for Aggressive Tumors.
Spatial Immunoprofiling of Adenoid Cystic Carcinoma Reveals B7-H4 Is a Therapeutic Target for Aggressive Tumors.
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腺样囊性癌的空间免疫分析揭示 B7-H4 是侵袭性肿瘤的治疗靶点。
DOI：
10.1158/1078-0432.ccr-23-0514
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Bel
中科院分区：
文献类型：
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作者：
Sousa,LuanaGuimaraes;McGrail,DanielJ;LazarNeto,Felippe;Li,Kaiyi;Marques-Piubelli,MarioL;Ferri-Borgogno,Sammy;Dai,Hui;Mitani,Yoshitsugu;SpardyBurr,Nicole;Cooper,ZacharyA;Kinneer,Krista;Cortez,MariaAngelica;Lin,Shiaw-Yih;Bel
目的腺样囊性癌(ACC)是一种异质性恶性肿瘤，目前尚无有效的系统治疗方法来治疗转移性疾病。我们之前描述了两种具有不同治疗易感性的预后ACC分子亚型，ACC-I和ACC-II。在这项研究中，我们使用RNA测序和空间生物学来探索ACC肿瘤微环境(TME)以确定潜在的治疗靶点。实验设计来自62名ACC患者的肿瘤样本，这些样本具有可用的RNA测序数据，作为先前研究的一部分，用一组28个有效的金属标记抗体进行染色。采用Fluidigm Helios CyTOF细胞仪进行图像质量分析(IMC)，并用Visiopamm软件进行统计分析。B7-H4抗体-药物结合物AZD8205在ACC患者来源的异种移植物(PDX)上进行了测试。结果RNA去卷积显示大多数AC细胞在免疫上是“冷的”，大约30%是“热的”。预后不良的ACC-I肿瘤具有较高的免疫细胞密度；然而，IMC的空间分析显示，ACC-I免疫细胞明显局限于间质，表现为免疫排斥的TME。ACC-I肿瘤过度表达免疫检查点B7-H4，免疫排斥程度与B7-H4表达水平直接相关，B7-H4表达水平是生存不良的独立预测因素。两个ACC-I/B7-H4高PDX对单剂AZD8205的完全应答率为90%，但在同种类型结合的有效载荷和ACC-II/B7-H4低PDX中均未观察到。结论空间分析显示ACC亚型具有明显的TME，其免疫细胞丰富，局限于基质。B7-H4在预后不良的ACC-I亚型中高表达，是一个潜在的治疗靶点。
PurposeAdenoid cystic carcinoma (ACC) is a heterogeneous malignancy, and no effective systemic therapy exists for metastatic disease. We previously described two prognostic ACC molecular subtypes with distinct therapeutic vulnerabilities, ACC-I and ACC-II. In this study, we explored the ACC tumor microenvironment (TME) using RNA-sequencing and spatial biology to identify potential therapeutic targets.Experimental DesignTumor samples from 62 ACC patients with available RNA-sequencing data that had been collected as part of previous studies were stained with a panel of 28 validated metal-tagged antibodies. Imaging mass cytometry (IMC) was performed using the Fluidigm Helios CyTOF instrument and analyzed with Visiopharm software. The B7-H4 antibody–drug conjugate AZD8205 was tested in ACC patient-derived xenografts (PDX).ResultsRNA deconvolution revealed that most ACCs are immunologically “cold,” with approximately 30% being “hot.” ACC-I tumors with a poor prognosis harbored a higher density of immune cells; however, spatial analysis by IMC revealed that ACC-I immune cells were significantly restricted to the stroma, characterizing an immune-excluded TME. ACC-I tumors overexpressed the immune checkpoint B7-H4, and the degree of immune exclusion was directly correlated with B7-H4 expression levels, an independent predictor of poor survival. Two ACC-I/B7-H4-high PDXs obtained 90% complete responses to a single dose of AZD8205, but none were observed with isotype-conjugated payload or in an ACC-II/B7-H4 low PDX.ConclusionsSpatial analysis revealed that ACC subtypes have distinct TMEs, with enrichment of ACC-I immune cells that are restricted to the stroma. B7-H4 is highly expressed in poor-prognosis ACC-I subtype and is a potential therapeutic target.