ELTD1/ADGRL4 expression is increased in the vasculature of a number of tumor types and this correlates with a good prognosis. Expression has also been reported in some tumor cells with high expression correlating with a good prognosis in hepatocellular carcinoma (HCC) and a poor prognosis in glioblastoma. Here we show that 35% of primary human breast tumors stain positively for ELTD1, with 9% having high expression that correlates with improved relapse-free survival. Using immunocompetent, syngeneic mouse breast cancer models we found that tumors expressing recombinant murine Eltd1 grew faster than controls, with an enhanced ability to metastasize and promote systemic immune effects. The Eltd1-expressing tumors had larger and better perfused vessels and tumor–endothelial cell interaction led to the release of proangiogenic and immune-modulating factors. M2-like macrophages increased in the stroma along with expression of programmed death-ligand 1 (PD-L1) on tumor and immune cells, to create an immunosuppressive microenvironment that allowed Eltd1-regulated tumor growth in the presence of an NY-ESO-1–specific immune response. Eltd1-positive tumors also responded better to chemotherapy which could explain the relationship to a good prognosis observed in primary human cases. Thus, ELTD1 expression may enhance delivery of therapeutic antibodies to reverse the immunosuppression and increase response to chemotherapy and radiotherapy in this subset of tumors. ELTD1 may be useful as a selection marker for such therapies. Implications: ELTD1 expression in mouse breast tumors creates an immunosuppressive microenvironment and increases vessel size and perfusion. Its expression may enhance the delivery of therapies targeting the immune system.

中文翻译：

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ADGRL4/ELTD1 在乳腺癌细胞中的表达诱导血管正常化和免疫抑制

ELTD1/ADGRL4 表达在许多肿瘤类型的脉管系统中增加，这与良好的预后相关。在一些肿瘤细胞中也报道了表达，其高表达与肝细胞癌 (HCC) 的良好预后和胶质母细胞瘤的不良预后相关。在这里，我们显示 35% 的原发性人类乳腺肿瘤对 ELTD1 染色呈阳性，其中 9% 具有与改善的无复发生存相关的高表达。使用具有免疫活性的同基因小鼠乳腺癌模型，我们发现表达重组鼠 Eltd1 的肿瘤比对照生长得更快，转移和促进全身免疫效应的能力增强。表达 Eltd1 的肿瘤具有更大和更好的灌注血管，肿瘤-内皮细胞相互作用导致促血管生成和免疫调节因子的释放。基质中的 M2 样巨噬细胞随着程序性死亡配体 1 (PD-L1) 在肿瘤和免疫细胞上的表达而增加，以创造一个免疫抑制微环境，允许 Eltd1 在 NY-ESO-1 存在下调节肿瘤生长——特异性免疫反应。Eltd1 阳性肿瘤对化疗的反应也更好，这可以解释与在原发性人类病例中观察到的良好预后的关系。因此，ELTD1 表达可能会增强治疗性抗体的传递，以逆转免疫抑制并增加对这部分肿瘤的化学疗法和放射疗法的反应。ELTD1 可用作此类疗法的选择标记。影响：ELTD1 在小鼠乳腺肿瘤中的表达会产生免疫抑制微环境并增加血管大小和灌注。它的表达可能会增强针对免疫系统的疗法的传递。