Host responses to tumor cells include tumor suppressing or promoting mechanisms. We sought to detail the effect of Hedgehog (Hh) pathway inhibition on the composition of the mammary tumor immune portfolio. We hypothesized that Hh signaling mediates a crosstalk between breast cancer cells and macrophages that dictates alternative polarization of macrophages and consequently supports a tumor-promoting microenvironment. We used an immunocompetent, syngeneic mouse mammary cancer model to inhibit Hh signaling with the pharmacological inhibitor, Vismodegib. Using molecular and functional assays, we identified that Hedgehog (Hh) signaling mediates a molecular crosstalk between mammary cancer cells and macrophages that culminates in alternative polarization of macrophages. We carried out an unbiased kinomics and genomics assessment to unravel changes in global kinomic and gene signatures impacted by Hh signaling. Our investigations reveal that in an immunocompetent mammary cancer model, the administration of Vismodegib led to changes in the portfolio of tumor-infiltrating immune cells. This was characterized by a marked reduction in immune-suppressive innate and adaptive cells concomitant with an enrichment of cytotoxic immune cells. Breast cancer cells induce M2 polarization of macrophages via a crosstalk mediated by Hh ligands that alters critical kinomic and genomic signatures. Macrophage depletion improved the benefit of Hedgehog inhibition on eliciting an immunogenic, pro-inflammatory profile. We define a novel role for Hh signaling in disabling anti-tumor immunity. Inhibition of Hh signaling presents with dual advantages of tumor cell-targeting as well as re-educating a dysfunctional tumor microenvironment.

中文翻译：

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抑制 Hedgehog 信号可重新编程乳腺癌中功能失调的免疫微环境。


宿主对肿瘤细胞的反应包括肿瘤抑制或促进机制。我们试图详细说明 Hedgehog (Hh) 通路抑制对乳腺肿瘤免疫组合组成的影响。我们假设 Hh 信号传导介导乳腺癌细胞和巨噬细胞之间的串扰，从而决定巨噬细胞的替代极化，从而支持促进肿瘤生长的微环境。我们使用具有免疫功能的同基因小鼠乳腺癌模型，通过药理学抑制剂 Vismodegib 抑制 Hh 信号传导。通过分子和功能分析，我们发现刺猬 (Hh) 信号传导介导乳腺癌细胞和巨噬细胞之间的分子串扰，最终导致巨噬细胞的交替极化。我们进行了公正的运动组学和基因组学评估，以揭示受 Hh 信号传导影响的全局运动组学和基因特征的变化。我们的研究表明，在免疫功能正常的乳腺癌模型中，给予 Vismodegib 导致肿瘤浸润免疫细胞组合发生变化。其特征是免疫抑制性先天性和适应性细胞显着减少，同时细胞毒性免疫细胞增多。乳腺癌细胞通过 Hh 配体介导的串扰诱导巨噬细胞的 M2 极化，从而改变关键的基因组和基因组特征。巨噬细胞耗竭提高了 Hedgehog 抑制在引发免疫原性、促炎性方面的益处。我们定义了 Hh 信号传导在禁用抗肿瘤免疫方面的新作用。抑制 Hh 信号传导具有肿瘤细胞靶向以及重新教育功能失调的肿瘤微环境的双重优势。