Depletion of immunosuppressive tumor-associated macrophages (TAMs) or reprogramming toward a proinflammatory activation state represent different strategies to therapeutically target this abundant myeloid population. In this study, we report that inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling sensitizes TAMs to profound and rapid reprogramming in the presence of a CD40 agonist before their depletion. Despite the short-lived nature of macrophage hyperactivation, combined CSF-1R+CD40 stimulation of macrophages is sufficient to create a proinflammatory tumor milieu that reinvigorates an effective T cell response in transplanted tumors that are either responsive or insensitive to immune checkpoint blockade. The central role of macrophages in regulating preexisting immunity is substantiated by depletion experiments, transcriptome analysis of ex vivo sorted TAMs, and gene expression profiling of whole tumor lysates at an early treatment time point. This approach enabled the identification of specific combination-induced changes among the pleiotropic activation spectrum of the CD40 agonist. In patients, CD40 expression on human TAMs was detected in mesothelioma and colorectal adenocarcinoma.

免疫抑制性肿瘤相关巨噬细胞（TAM）的耗竭或向炎症激活状态的重新编程代表了以治疗为目标的大量髓样人群的不同策略。在这项研究中，我们报告抑制集落刺激因子1受体（CSF-1R）信号使TAM在CD40激动剂耗尽前对深刻而迅速的重编程敏感。尽管巨噬细胞过度活化的短暂性，CSF-1R + CD40对巨噬细胞的联合刺激足以产生促炎性肿瘤环境，从而在对免疫检查点封锁有反应性或不敏感的移植性肿瘤中重新激发有效的T细胞反应。耗竭实验证实了巨噬细胞在调节已有免疫力中的核心作用，体外TAM的转录组分析，以及在早期治疗时间点对整个肿瘤溶解产物进行基因表达谱分析。该方法使得能够鉴定CD40激动剂的多效性活化谱中特定的组合诱导的变化。在患者中，在间皮瘤和大肠腺癌中检测到人TAM上的CD40表达。