The interplay between cancer cells and immune cells is a key determinant of tumor survival. Here, we uncovered how tumors exploit the immunomodulatory properties of the extracellular matrix to create a microenvironment that enables their escape from immune surveillance. Using orthotopic grafting of mammary tumor cells in immunocompetent mice and autochthonous models of breast cancer, we discovered how tenascin-C, a matrix molecule absent from most healthy adult tissues but expressed at high levels and associated with poor patient prognosis in many solid cancers, controls the immune status of the tumor microenvironment. We found that, although host-derived tenascin-C promoted immunity via recruitment of proinflammatory, antitumoral macrophages, tumor-derived tenascin-C subverted host defense by polarizing tumor-associated macrophages toward a pathogenic, immune-suppressive phenotype. Therapeutic monoclonal antibodies that blocked tenascin-C activation of Toll-like receptor 4 reversed this phenotypic switch in vitro and reduced tumor growth and lung metastasis in vivo, providing enhanced benefit in combination with anti-PD-L1 over either treatment alone. Combined tenascin-C:macrophage gene-expression signatures delineated a significant survival benefit in people with breast cancer. These data revealed a new approach to targeting tumor-specific macrophage polarization that may be effective in controlling the growth and spread of breast tumors.

中文翻译：

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靶向基质的免疫疗法通过切换巨噬细胞表型来控制肿瘤的生长和扩散。

癌细胞和免疫细胞之间的相互作用是肿瘤存活的关键决定因素。在这里，我们发现了肿瘤如何利用细胞外基质的免疫调节特性来创建微环境，从而使其能够逃避免疫监视。在免疫功能正常的小鼠和乳腺癌的本地模型中，通过原位移植乳腺肿瘤细胞，我们发现tenascin-C是大多数健康成人组织中缺乏的基质分子，但在许多实体癌中均表现为高水平表达并与患者预后不良相关，对照肿瘤微环境的免疫状态。我们发现，尽管宿主来源的腱生蛋白C通过募集促炎性，抗肿瘤性巨噬细胞来增强免疫力，通过使肿瘤相关的巨噬细胞偏向致病的，免疫抑制的表型，来源于肿瘤的腱糖蛋白C破坏了宿主防御。阻断Tenascin-C激活Toll样受体4的治疗性单克隆抗体在体外逆转了这种表型转换，并在体内降低了肿瘤的生长和肺转移，与抗PD-L1联合使用比单独使用任何一种治疗方法都具有更高的获益。结合的腱生蛋白C：巨噬细胞基因表达特征描述了乳腺癌患者的显着生存获益。这些数据揭示了靶向肿瘤特异性巨噬细胞极化的新方法，该方法可能有效地控制了乳腺肿瘤的生长和扩散。阻断Tenascin-C激活Toll样受体4的治疗性单克隆抗体在体外逆转了这种表型转换，并在体内降低了肿瘤的生长和肺转移，与抗PD-L1联合使用比单独使用任何一种治疗方法都具有更高的获益。结合的腱生蛋白C：巨噬细胞基因表达特征描述了乳腺癌患者的显着生存获益。这些数据揭示了靶向肿瘤特异性巨噬细胞极化的新方法，该方法可能有效控制乳腺肿瘤的生长和扩散。阻断Tenascin-C激活Toll样受体4的治疗性单克隆抗体在体外逆转了这种表型转换，并在体内降低了肿瘤的生长和肺转移，与抗PD-L1联合使用比单独使用任何一种治疗方法都具有更高的获益。结合的腱生蛋白C：巨噬细胞基因表达特征描述了乳腺癌患者的显着生存获益。这些数据揭示了靶向肿瘤特异性巨噬细胞极化的新方法，该方法可能有效控制乳腺肿瘤的生长和扩散。