Regenerative Processing Plant, LLC, 34176 US Highway 19 N Palm Harbor, FL 34684, USA.
Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia.
Anal Cell Pathol (Amst). 2022 Jun 15;2022:3655595. doi: 10.1155/2022/3655595. eCollection 2022.
Breast cancer is considered refractory to immunotherapy. Accordingly, there is an urgent need for the therapeutic use of new immunostimulatory agents which would enhance antitumor immune response against breast cancer cells. "Derived Multiple Allogeneic Protein Paracrine Signaling (d-MAPPS)" is a biological product whose activity is based on chemokines and cytokines that modulate homing and phenotype of immune cells. d-MAPPS contains high concentration of dendritic cell (DC) and T cell-attracting chemokine CXCL16 and potent T cell-activating cytokine IL-27 which enhance DC:T cell cross-talk in inflamed tissues. Herewith, we used 4T1 murine model of breast cancer to analyze d-MAPPS-dependent enhancement of T cell-driven antitumor immunity. 4T1+d-MAPPS-treated mice showed delayed mammary tumor appearance compared to 4T1+saline-treated animals. d-MAPPS significantly reduced tumor weight and volume and improved survival of 4T1-treated mice. Significantly increased concentration of CXCL16, IL-27, IFN-, and IL-17 and decreased concentration of immunosuppressive TGF- and IL-10 were measured in serum samples and tumor tissues of 4T1+d-MAPPS-treated mice. d-MAPPS enhanced production of IL-12 and increased expression of MHC class II and costimulatory molecules on tumor-infiltrated DC, significantly improving their antigen-presenting properties. d-MAPPS in CXCL16-dependent manner promoted recruitment of antitumorigenic IFN-/IL-17-producing CD4+Th1/Th17 cells and in IL-27-dependent manner induced expansion of tumoricidal CD178+granzyme B-expressing CD8+CTLs and inhibited generation of tolerogenic DC, IL-10, and TGF--producing FoxP3-expressing T regulatory cells. In summing up, d-MAPPS, in CXL16- and IL-27-dependent manner, enhanced T cell-driven antitumor immune response and suppressed breast cancer growth in experimental mice.
乳腺癌被认为对免疫疗法有抗性。因此，迫切需要使用新的免疫刺激剂进行治疗，以增强针对乳腺癌细胞的抗肿瘤免疫反应。“衍生的多种同种蛋白旁分泌信号（d-MAPPS）”是一种生物制品，其活性基于趋化因子和细胞因子，可调节免疫细胞的归巢和表型。d-MAPPS 含有高浓度的树突状细胞（DC）和 T 细胞吸引趋化因子 CXCL16 和有效的 T 细胞激活细胞因子 IL-27，可增强炎症组织中 DC：T 细胞的串扰。在此，我们使用 4T1 小鼠乳腺癌模型分析 d-MAPPS 依赖性增强 T 细胞驱动的抗肿瘤免疫。与 4T1+生理盐水处理的动物相比，4T1+d-MAPPS 处理的小鼠出现乳腺肿瘤的时间延迟。d-MAPPS 显著降低了肿瘤的重量和体积，并改善了 4T1 处理小鼠的存活率。在 4T1+d-MAPPS 处理的小鼠的血清样本和肿瘤组织中，测量到 CXCL16、IL-27、IFN-和 IL-17 的浓度显著增加，而免疫抑制性 TGF-和 IL-10 的浓度降低。d-MAPPS 增强了 IL-12 的产生，并增加了肿瘤浸润性 DC 上 MHC 类 II 和共刺激分子的表达，显著改善了它们的抗原呈递特性。d-MAPPS 以 CXCL16 依赖的方式促进抗肿瘤 IFN-/IL-17 产生的 CD4+Th1/Th17 细胞的募集，并以 IL-27 依赖的方式诱导杀伤性 CD178+颗粒酶 B 表达的 CD8+CTL 的扩增，并抑制耐受生成性 DC、IL-10 和 TGF--产生 FoxP3 表达的 T 调节细胞。总之，d-MAPPS 以 CXCL16 和 IL-27 依赖的方式增强了 T 细胞驱动的抗肿瘤免疫反应，并抑制了实验小鼠中的乳腺癌生长。
