Claudin-low breast cancer is an aggressive subtype that confers poor prognosis and is found largely within the clinical triple-negative group of breast cancer patients. Here, we have shown that intrinsic and immune cell gene signatures distinguish the claudin-low subtype clinically as well as in mouse models of other breast cancer subtypes. Despite adaptive immune cell infiltration in claudin-low tumors, treatment with immune checkpoint inhibitory antibodies against cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed death receptor 1 (PD-1) were ineffective in controlling tumor growth. CD4⁺FoxP3⁺ Tregs represented a large proportion of the tumor-infiltrating lymphocytes (TILs) in claudin-low tumors, and Tregs isolated from tumor-bearing mice were able to suppress effector T cell responses. Tregs in the tumor microenvironment highly expressed PD-1 and were recruited partly through tumor generation of the chemokine CXCL12. Antitumor efficacy required stringent Treg depletion combined with checkpoint inhibition; delays in tumor growth were not observed using therapies that modestly diminished the number of Tregs in the tumor microenvironment. This study provides evidence that the recruitment of Tregs to the tumor microenvironment inhibits an effective antitumor immune response and highlights early Treg recruitment as a possible mechanism for the lack of response to immune checkpoint blockade antibodies in specific subtypes of cancer that are heavily infiltrated with adaptive immune cells.

中文翻译：

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Treg耗竭增强克劳丁低乳腺癌中的检查点抑制。

克劳丁低度乳腺癌是一种侵袭性亚型，预后较差，主要在临床三阴性乳腺癌患者中发现。在这里，我们已经显示出内在的和免疫细胞基因特征可以在临床上以及其他乳腺癌亚型的小鼠模型中区分claudin-low亚型。尽管在克劳丁含量低的肿瘤中具有适应性免疫细胞浸润，但针对细胞毒性T淋巴细胞相关蛋白4（CTLA-4）和程序性死亡受体1（PD-1）的免疫检查点抑制抗体的治疗仍无法有效控制肿瘤的生长。CD4 ⁺ FoxP3 ⁺Tregs在克劳丁含量低的肿瘤中代表了大部分的肿瘤浸润淋巴细胞（TILs），并且从荷瘤小鼠中分离出的Tregs能够抑制效应T细胞反应。肿瘤微环境中的Tregs高表达PD-1，并部分通过趋化因子CXCL12的肿瘤生成而被募集。抗肿瘤药效要求严格的Treg耗竭并结合检查点抑制作用；使用适度减少肿瘤微环境中Treg数量的疗法，未观察到肿瘤生长延迟。