EDIL3 as an Angiogenic Target of Immune Exclusion Following Checkpoint Blockade.
EDIL3 as an Angiogenic Target of Immune Exclusion Following Checkpoint Blockade.
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DOI：
10.1158/2326-6066.cir-23-0171
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发表时间：
2023-11-01
影响因子：
10.1
通讯作者：
Hodi, F. Stephen
中科院分区：
文献类型：
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作者：
Tabasum, Saba;Thapa, Dinesh;Giobbie-Hurder, Anita;Weirather, Jason L.;Campisi, Marco;Schol, Pieter J.;Li, Xiaoyu;Li, Jingjing;Yoon, Charles H.;Manos, Michael P.;Barbie, David A.;Hodi, F. Stephen
了解受益于伊匹单抗和贝伐珠单抗治疗的晚期黑色素瘤患者的免疫反应有望确定潜在的功能靶点。作者将免疫抑制性 CAF 中的 EDIL3 确定为推定的免疫原性靶点，与肿瘤微环境中 T 细胞免疫排斥相关。免疫检查点阻断（ICB）已成为多种实体瘤的治疗标准。已经研究了多种组合方法以提高治疗效果。抗血管生成剂和 ICB 的组合已证明对多种癌症有效。为了提高对这些治疗方式协同作用的机制的理解，我们对接受伊匹单抗和贝伐单抗治疗的长期缓解患者的血清进行了筛查。我们发现了针对 EGF 样重复序列和盘状蛋白 I 样结构域蛋白 3 (EDIL3) 的高滴度抗体反应，这与良好的临床结果相关。 EDIL3 是一种细胞外蛋白，之前被认为是各种恶性肿瘤预后不良的标志物。我们的肿瘤免疫功能障碍和排除分析预测，EDIL3 与细胞毒性免疫细胞浸润和对 ICB 无反应的免疫排除特征相关。癌症相关成纤维细胞 (CAF) 被预测为免疫排斥相关细胞中 EDIL3 的来源。此外，癌症基因组图谱皮肤黑色素瘤 (TCGA-SKCM) 和 CheckMate 064 数据分析将高水平的 EDIL3 与泛成纤维细胞 TGFβ 反应增强、血管生成特征富集以及上皮间质转化诱导相关。我们的体外研究验证了患者来源的 CAF 中的 EDIL3 过表达和 TGFβ 调节。在患者的治疗前血清样本中，EDIL3 的循环水平与 VEGF 的循环水平相关，并且与 VEGF 一样，EDIL3 增加了患者来源的肿瘤内皮细胞 (TEC) 的血管生成能力。从机制上讲，三维微流体培养和 TEC 二维迁移测定支持 EDIL3 介导的淋巴细胞功能相关抗原 1 (LFA-1)-ICAM-1 相互作用的破坏作为 T 细胞排斥的可能手段。我们建议 EDIL3 作为改善免疫细胞跨内皮迁移和 ICB 治疗疗效的潜在靶点。
Understanding immune responses in advanced melanoma patients benefitting from ipilimumab and bevacizumab treatment holds promise for identifying potential functional targets. The authors identify EDIL3 in immunosuppressive CAFs as a putative immunogenic target linked to T-cell immune exclusion from the tumor microenvironment. Immune checkpoint blockade (ICB) has become the standard of care for several solid tumors. Multiple combinatorial approaches have been studied to improve therapeutic efficacy. The combination of antiangiogenic agents and ICB has demonstrated efficacy in several cancers. To improve the mechanistic understanding of synergies with these treatment modalities, we performed screens of sera from long-term responding patients treated with ipilimumab and bevacizumab. We discovered a high-titer antibody response against EGF-like repeats and discoidin I–like domains protein 3 (EDIL3) that correlated with favorable clinical outcomes. EDIL3 is an extracellular protein, previously identified as a marker of poor prognosis in various malignancies. Our Tumor Immune Dysfunction and Exclusion analysis predicted that EDIL3 was associated with immune exclusion signatures for cytotoxic immune cell infiltration and nonresponse to ICB. Cancer-associated fibroblasts (CAF) were predicted as the source of EDIL3 in immune exclusion–related cells. Furthermore, The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) and CheckMate 064 data analyses correlated high levels of EDIL3 with increased pan-fibroblast TGFβ response, enrichment of angiogenic signatures, and induction of epithelial-to-mesenchymal transition. Our in vitro studies validated EDIL3 overexpression and TGFβ regulation in patient-derived CAFs. In pretreatment serum samples from patients, circulating levels of EDIL3 were associated with circulating levels of VEGF, and like VEGF, EDIL3 increased the angiogenic abilities of patient-derived tumor endothelial cells (TEC). Mechanistically, three-dimensional microfluidic cultures and two-dimensional transmigration assays with TEC endorsed EDIL3-mediated disruption of the lymphocyte function-associated antigen-1 (LFA-1)–ICAM-1 interaction as a possible means of T-cell exclusion. We propose EDIL3 as a potential target for improving the transendothelial migration of immune cells and efficacy of ICB therapy.