作为一种免疫佐剂，原发性异种受体细胞（AlloDCs）在多项临床前和临床研究中展现出有希望的免疫前驱效应。包括NK细胞和T细胞在内的效应细胞因其有选择性地识别和清除恶性细胞的能力而被广泛认可，被视为癌症免疫治疗有效性的关键因素。4-1BB作为一个共刺激受体，在促进效应细胞活化中发挥着重要作用。本研究评估了将免疫佐剂AlloDCs以肿瘤内给药的方式与系统性α4-1BB治疗直接作用于效应细胞相结合时的抗肿瘤效应。在CT-26小鼠结肠癌模型和B16小鼠黑色素瘤模型中，AlloDCs显著提高了α4-1BB抗体的治疗效果。通过延缓肿瘤生长和延长生存期观察到了这种增强效果。联合治疗组肿瘤微环境（TME）分析显示增加了活化的内源性DC和IFNγ+ CD8+ T细胞的浸润，减少了疲惫的迹象。此外，组合治疗还增加了组织驻留存储（TRM）CD8+ T细胞（CD103+CD49a+CD69+）的存在。联合治疗还导致CD39+CD103+肿瘤特异性CD8+ T细胞和新抗原特异性T细胞对肿瘤的浸润增加。此外，联合治疗还导致免疫抑制的肿瘤微环境减少，表现为髓源性抑制细胞和调节性T细胞的浸润减少。这些发现表明，将肿瘤内AlloDCs给药与系统性α4-1BB激动剂治疗相结合能够产生协同的抗肿瘤反应，因此值得通过临床研究进一步调查。 版权所有 © 2023 Ali, Gao, Iskantar, Wang, Karlsson-Parra, Yu 和 Jin。

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 (TRM) CD8+ T cells (CD103+CD49a+CD69+). The combination treatment also led to increased infiltration of CD39+CD103+ 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.Copyright © 2023 Ali, Gao, Iskantar, Wang, Karlsson-Parra, Yu and Jin.