Chemokines are key factors that influence the migration and maintenance of relevant immune cells into an infected tissue or a tumor microenvironment. Therefore, it is believed that the controlled administration of chemokines in the tumor microenvironment may be an effective immunotherapy against cancer. Previous studies have shown that CCL3, also known as macrophage inflammatory protein 1-alpha, facilitates the recruitment of dendritic cells (DCs) for the presentation of tumor Ags and promotes T cell activation. Here, we investigated the role of CCL3 in regulating the tumor microenvironment using a syngeneic mouse tumor model. We observed that MC38 tumors overexpressing CCL3 (CCL3-OE) showed rapid regression compared with the wild type MC38 tumors. Additionally, these CCL3-OE tumors showed an increase in the proliferative and functional tumor-infiltrating T cells. Furthermore, PD-1 immune checkpoint blockade accelerated tumor regression in the CCL3-OE tumor microenvironment. Next, we generated a modified CCL3 protein for pre-clinical use by fusing recombinant CCL3 (rCCL3) with a non-cytolytic hybrid Fc (HyFc). Administering a controlled dose of rCCL3-HyFc via subcutaneous injections near tumors was effective in tumor regression and improved survival along with activated myeloid cells and augmented T cell responses. Furthermore, combination therapy of rCCL3-HyFc with PD-1 blockade exhibited prominent effect to tumor regression. Collectively, our findings demonstrate that appropriate concentrations of CCL3 in the tumor microenvironment would be an effective adjuvant to promote anti-tumor immune responses, and suggest that administering a long-lasting form of CCL3 in combination with PD-1 blockers can have clinical applications in cancer immunotherapy.

中文翻译：

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在肿瘤微环境中富集 CCL3 可促进 T 细胞反应并提高抗 PD-1 疗法的功效。

趋化因子是影响相关免疫细胞迁移和维持到受感染组织或肿瘤微环境中的关键因素。因此，相信在肿瘤微环境中受控地施用趋化因子可能是一种有效的抗癌免疫疗法。先前的研究表明，CCL3，也称为巨噬细胞炎症蛋白 1-α，促进树突状细胞 (DC) 的募集以呈现肿瘤抗原并促进 T 细胞活化。在这里，我们使用同源小鼠肿瘤模型研究了 CCL3 在调节肿瘤微环境中的作用。我们观察到，与野生型 MC38 肿瘤相比，过表达 CCL3（CCL3-OE）的 MC38 肿瘤显示出快速消退。此外，这些 CCL3-OE 肿瘤显示增殖性和功能性肿瘤浸润性 T 细胞增加。此外，PD-1 免疫检查点阻断加速了 CCL3-OE 肿瘤微环境中的肿瘤消退。接下来，我们通过将重组 CCL3 (rCCL3) 与非溶细胞杂交 Fc (HyFc) 融合，生成了用于临床前使用的修饰 CCL3 蛋白。通过在肿瘤附近皮下注射控制剂量的 rCCL3-HyFc 可有效地使肿瘤消退并提高存活率，同时激活骨髓细胞并增强 T 细胞反应。此外，rCCL3-HyFc 与 PD-1 阻断剂的联合治疗对肿瘤消退具有显着影响。总的来说，我们的研究结果表明，在肿瘤微环境中适当浓度的 CCL3 将是促进抗肿瘤免疫反应的有效佐剂，