Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Chinese Academy of Science (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China.
Front Immunol. 2023 Aug 15;14:1146413. doi: 10.3389/fimmu.2023.1146413. eCollection 2023.
As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic α4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of α4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFNγ CD8 T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (T) CD8 T cells (CD103CD49aCD69). The combination treatment also led to increased infiltration of CD39CD103 tumor-specific CD8 T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic α4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.
作为一种免疫佐剂，促炎同种异体树突状细胞（AlloDCs）在多项临床前和临床研究中显示出了有希望的免疫启动效应。效应细胞，包括 NK 细胞和 T 细胞，由于其能够选择性识别和消除恶性细胞，被广泛认为是癌症免疫治疗有效性的关键因素。4-1BB 作为一种共刺激受体，在效应细胞激活的刺激中发挥重要作用。本研究评估了将免疫佐剂同种异体树突状细胞（AlloDCs）瘤内给药与直接作用于效应细胞的全身α4-1BB 治疗相结合时的抗肿瘤效果。在 CT-26 小鼠结肠癌细胞模型和 B16 小鼠黑色素瘤模型中，AlloDCs 显著增强了 α4-1BB 抗体的治疗效果。这种增强表现为肿瘤生长延迟和生存时间延长。联合治疗组肿瘤微环境（TME）的分析显示，TME 呈现免疫炎症特征，表现为激活的内源性 DC 和 IFNγ CD8 T 细胞浸润增加，衰竭迹象减少。此外，组织驻留记忆（T）CD8 T 细胞（CD103CD49aCD69）的数量也有所增加。联合治疗还导致肿瘤特异性 CD8 T 细胞和新抗原特异性 T 细胞中 CD39CD103 的浸润增加。此外，联合治疗导致肿瘤中髓源抑制细胞和 Treg 的浸润减少，表明 TME 免疫抑制程度降低。这些发现表明，同种异体树突状细胞（AlloDCs）瘤内给药与全身激动性α4-1BB 治疗相结合可以产生协同的抗肿瘤反应，因此值得通过临床研究进一步探讨。
