Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Cancer Immunol Immunother. 2023 Mar;72(3):719-731. doi: 10.1007/s00262-022-03276-4. Epub 2022 Sep 2.
In the tumor microenvironment (TME), one of the major functions of tumor-recruited CD11b cells are the suppression of the T-cell-mediated anti-tumor immune response. β-glucan could convert the phenotype of tumor-recruited CD11b cells from the suppressive to the promotive, and enhanced their anti-tumor effects. However, β-glucan could enhance the PD-1/PD-L1 expression on CD11b cells, while PD-1 could inhibit macrophage phagocytosis and PD-L1 could induce a co-inhibitory signal in T-cells and lead to T-cell apoptosis and anergy. These protumor effects may be reversed by PD-1/PD-L1 block therapy. In the present study, we focused on the efficacy of β-glucan anti-tumor therapy combined with anti-PD-L1 mAb treatment, and the mechanism of their synergistic effects could be fully verified. We verified the effect of β-glucan (i.e., inflammatory cytokine secretion of TNF-α, IL-12, IL-6, IL-1β and the expression of immune checkpoint PD-1/PD-L1) in naïve mouse peritoneal exudate CD11b cells. In our mouse melanoma model, treatment with a PD-L1 blocking antibody with β-glucan synergized tumor regression. After treatment with β-glucan and anti-PD-L1 mAb antibody, tumor infiltrating leukocyte (TILs) not only showed a competent T-cell function (CD107a, perforin, IL-2, IFN-γ and Ki67) and CTL population, but also showed enhanced tumor-recruited CD11b cell activity (IL-12, IL-6, IL-1β and PD-1). This effect was also verified in the peritoneal exudate CD11b cells of tumor-bearing mice. PD-1/PD-L1 blockade therapy enhanced the β-glucan antitumor effects via the blockade of tumor-recruited CD11b cell immune checkpoints in the melanoma model.
在肿瘤微环境（TME）中，肿瘤募集的 CD11b 细胞的主要功能之一是抑制 T 细胞介导的抗肿瘤免疫反应。β-葡聚糖可以将肿瘤募集的 CD11b 细胞的表型从抑制型转变为促进型，并增强其抗肿瘤作用。然而，β-葡聚糖可以增强 CD11b 细胞上的 PD-1/PD-L1 表达，而 PD-1 可以抑制巨噬细胞吞噬作用，PD-L1 可以在 T 细胞中诱导共抑制信号，导致 T 细胞凋亡和无能。这些促进肿瘤的作用可能被 PD-1/PD-L1 阻断治疗逆转。在本研究中，我们专注于β-葡聚糖抗肿瘤治疗联合抗 PD-L1 mAb 治疗的疗效，并充分验证了它们协同作用的机制。我们验证了β-葡聚糖（即 TNF-α、IL-12、IL-6、IL-1β 的炎症细胞因子分泌和免疫检查点 PD-1/PD-L1 的表达）对幼稚小鼠腹腔渗出液 CD11b 细胞的作用。在我们的小鼠黑色素瘤模型中，用 PD-L1 阻断抗体与β-葡聚糖联合治疗可协同促进肿瘤消退。用β-葡聚糖和抗 PD-L1 mAb 抗体治疗后，肿瘤浸润白细胞（TILs）不仅表现出有能力的 T 细胞功能（CD107a、穿孔素、IL-2、IFN-γ 和 Ki67）和 CTL 群体，而且还表现出增强的肿瘤募集的 CD11b 细胞活性（IL-12、IL-6、IL-1β 和 PD-1）。在荷瘤小鼠的腹腔渗出液 CD11b 细胞中也验证了这一作用。PD-1/PD-L1 阻断治疗通过阻断黑色素瘤模型中肿瘤募集的 CD11b 细胞免疫检查点，增强了β-葡聚糖的抗肿瘤作用。
