Key Points Intratumoral 41BB agonism induces tumor regression in mouse models. 41BB agonism potentiates myeloid-mediated costimulation in tumors. Activation of 41BBL but not 41BB in human APCs promotes costimulatory responses. The activation of 41BB costimulatory signals by agonistic Abs enhances the expansion and function of tumor-infiltrating lymphocytes (TILs) for treating cancer patients with adoptive cell therapy. However, the impact of 41BB agonism is not limited to enhancing the activity of T cells, and the mechanism by which additional activation of this costimulatory axis in tumor-associated myeloid cells is poorly understood. In this study, we describe that the intratumoral administration of 41BB agonistic Abs led to increases in CD8 T cell infiltration followed by tumor regression in murine models. We found that granulocytes and monocytes rapidly replaced macrophages and dendritic cells in tumors following administration of anti-41BB Abs. Overall, myeloid cells from anti-41BB–treated tumors had an improved capacity to stimulate T cells in comparison with control-treated tumors. In human coculture systems, we demonstrated that the agonism of the 41BB–41BBL axis enhanced costimulatory signals and effector functions among APC and autologous TILs. Overall, these findings suggest that the effect of 41BB agonistic Abs are supported by additional costimulatory signals from tumor-associated myeloid cells,v leading to enhanced TIL expansion and function.

中文翻译：

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41BB 共刺激信号的瘤内激活增强 CD8 T 细胞扩增并调节肿瘤浸润性骨髓细胞

关键点 瘤内 41BB 激动剂在小鼠模型中诱导肿瘤消退。41BB 激动增强了肿瘤中髓样介导的共刺激。人类 APC 中 41BBL 而非 41BB 的激活促进了共刺激反应。激动性抗体对 41BB 共刺激信号的激活增强了肿瘤浸润淋巴细胞 (TIL) 的扩增和功能，用于使用过继细胞疗法治疗癌症患者。然而，41BB 激动的影响不仅限于增强 T 细胞的活性，而且对肿瘤相关骨髓细胞中这种共刺激轴额外激活的机制知之甚少。在这项研究中，我们描述了 41BB 激动剂 Abs 的肿瘤内给药导致 CD8 T 细胞浸润增加，随后小鼠模型中的肿瘤消退。我们发现，在施用抗 41BB 抗体后，粒细胞和单核细胞迅速取代了肿瘤中的巨噬细胞和树突细胞。总体而言，与对照治疗的肿瘤相比，来自抗 41BB 治疗的肿瘤的髓样细胞刺激 T 细胞的能力有所提高。在人类共培养系统中，我们证明 41BB-41BBL 轴的激动增强了 APC 和自体 TIL 之间的共刺激信号和效应器功能。总体而言，这些发现表明 41BB 激动性抗体的作用得到了来自肿瘤相关骨髓细胞的额外共刺激信号的支持，v 导致 TIL 扩增和功能增强。与对照治疗的肿瘤相比，来自抗 41BB 治疗肿瘤的骨髓细胞刺激 T 细胞的能力有所提高。在人类共培养系统中，我们证明 41BB-41BBL 轴的激动增强了 APC 和自体 TIL 之间的共刺激信号和效应器功能。总体而言，这些发现表明 41BB 激动性抗体的作用得到了来自肿瘤相关骨髓细胞的额外共刺激信号的支持，v 导致 TIL 扩增和功能增强。与对照治疗的肿瘤相比，来自抗 41BB 治疗肿瘤的骨髓细胞刺激 T 细胞的能力有所提高。在人类共培养系统中，我们证明 41BB-41BBL 轴的激动增强了 APC 和自体 TIL 之间的共刺激信号和效应器功能。总体而言，这些发现表明 41BB 激动性抗体的作用得到了来自肿瘤相关骨髓细胞的额外共刺激信号的支持，v 导致 TIL 扩增和功能增强。