Abstract Macrophages represent the most abundant immune component of the tumor microenvironment and often exhibit protumorigenic (M2-like) phenotypes that contribute to disease progression. Despite their generally accepted protumorigenic role, macrophages can also display tumoricidal (or M1-like) behavior, revealing that macrophages can be functionally reprogrammed, depending on the cues received within the tumor microenvironment. Moreover, such plasticity may be achieved by pharmacologic or biologic interventions. To that end, we previously demonstrated that a novel immunomodulator termed the “very small size particle” (VSSP) facilitates maturation of dendritic cells and differentiation of myeloid-derived suppressor cells to APCs with reduced suppressive activity in cancer models. VSSP was further shown to act in the bone marrow to drive the differentiation of progenitors toward monocytes, macrophages, and dendritic cells during emergency myelopoiesis. However, the underlying mechanisms for VSSP-driven alterations in myeloid differentiation and function remained unclear. In this study, in mouse models, we focused on macrophages and tested the hypothesis that VSSP drives macrophages toward M1-like functional states via IRF8- and PU.1-dependent mechanisms. We further hypothesized that such VSSP-mediated actions would be accompanied by enhanced antitumor responses. Overall, we showed that (1) VSSP drives naive or M2-derived macrophages to M1-like states, (2) the M1-like state induced by VSSP occurs via IRF8- and PU.1-dependent mechanisms, and (3) single-agent VSSP induces an antitumor response that is accompanied by alterations in the intratumoral myeloid compartment. These results provide a deeper mechanistic underpinning of VSSP and strengthen its use to drive M1-like responses in host defense, including cancer.

中文翻译：

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基于细菌和神经节苷脂的纳米颗粒启动巨噬细胞重编程并促进抗肿瘤表型

摘要巨噬细胞代表肿瘤微环境中最丰富的免疫成分，通常表现出促进疾病进展的促肿瘤（M2 样）表型。尽管巨噬细胞具有公认的促肿瘤作用，但它也可以表现出杀肿瘤（或 M1 样）行为，这表明巨噬细胞可以根据肿瘤微环境中收到的线索进行功能性重编程。此外，这种可塑性可以通过药理学或生物学干预来实现。为此，我们之前证明了一种称为“极小尺寸颗粒”（VSSP）的新型免疫调节剂可促进树突状细胞的成熟以及骨髓源性抑制细胞向 APC 的分化，并在癌症模型中降低抑制活性。VSSP 进一步被证明在骨髓中发挥作用，在紧急骨髓生成过程中驱动祖细胞分化为单核细胞、巨噬细胞和树突状细胞。然而，VSSP 驱动的骨髓分化和功能改变的潜在机制仍不清楚。在本研究中，我们在小鼠模型中重点关注巨噬细胞，并测试了 VSSP 通过 IRF8 和 PU.1 依赖机制驱动巨噬细胞向 M1 样功能状态发展的假设。我们进一步假设这种 VSSP 介导的作用将伴随增强的抗肿瘤反应。总体而言，我们表明（1）VSSP 驱动初始或 M2 衍生的巨噬细胞达到 M1 样状态，（2）VSSP 诱导的 M1 样状态通过 IRF8 和 PU.1 依赖机制发生，以及（3）单一VSSP 剂诱导抗肿瘤反应，并伴随着肿瘤内骨髓室的改变。这些结果为 VSSP 提供了更深入的机制基础，并加强了其在宿主防御（包括癌症）中驱动 M1 样反应的用途。