Neutrophils, the most abundant innate immune cells, function as crucial regulators of the adaptive immune system in diverse pathological conditions, including metastatic cancer. However, it remains largely unknown whether their immunomodulatory functions are intrinsic or acquired within the pathological tissue environment. Here, using mouse models of metastatic breast cancer in the lungs, we show that, although neutrophils isolated from bone marrow (BM) or blood are minimally immunosuppressive, lung-infiltrating neutrophils are robustly suppressive of both T cells and natural killer (NK) cells. We found that this tissue-specific immunosuppressive capacity of neutrophils exists in the steady state and is reinforced by tumor-associated inflammation. Acquisition of potent immunosuppression activity by lung-infiltrating neutrophils was endowed by the lung-resident stroma, specifically CD140a + mesenchymal cells (MCs) and largely via prostaglandin-endoperoxide synthase 2 (PTGS2), the rate-limiting enzyme for prostaglandin E 2 (PGE 2 ) biosynthesis. MC-specific deletion of Ptgs2 or pharmacological inhibition of PGE 2 receptors reversed lung neutrophil–mediated immunosuppression and mitigated lung metastasis of breast cancer in vivo. These lung stroma–targeting strategies substantially improved the therapeutic efficacy of adoptive T cell–based immunotherapy in treating metastatic disease in mice. Collectively, our results reveal that the immunoregulatory effects of neutrophils are induced by tissue-resident stroma and that targeting tissue-specific stromal factors represents an effective approach to boost tissue-resident immunity against metastatic disease.

中文翻译：

---

肺间充质细胞对中性粒细胞的免疫抑制重编程促进乳腺癌转移

中性粒细胞是最丰富的先天免疫细胞，在包括转移性癌症在内的多种病理条件下充当适应性免疫系统的重要调节因子。然而，它们的免疫调节功能是内在的还是在病理组织环境中获得的，目前仍不清楚。在这里，我们使用肺部转移性乳腺癌小鼠模型表明，尽管从骨髓 (BM) 或血液中分离的中性粒细胞具有最低限度的免疫抑制作用，但肺部浸润性中性粒细胞对 T 细胞和自然杀伤 (NK) 细胞具有强烈的抑制作用。我们发现中性粒细胞的这种组织特异性免疫抑制能力存在于稳定状态，并且通过肿瘤相关炎症得到加强。肺浸润中性粒细胞获得有效的免疫抑制活性是由肺驻留基质（特别是 CD140a）赋予的+间充质细胞 (MC)，主要通过前列腺素内过氧化物合酶 2 (PTGS2)，前列腺素 E 的限速酶2(前列腺素E2）生物合成。MC 特有的删除目标2或 PGE 的药理学抑制2受体逆转肺中性粒细胞介导的免疫抑制并减轻体内乳腺癌的肺转移。这些肺基质靶向策略大大提高了基于过继性 T 细胞的免疫疗法治疗小鼠转移性疾病的疗效。总的来说，我们的结果表明，中性粒细胞的免疫调节作用是由组织驻留基质诱导的，而针对组织特异性基质因子代表了增强组织驻留免疫力以对抗转移性疾病的有效方法。