Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden.
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):32005-32016. doi: 10.1073/pnas.2015343117. Epub 2020 Nov 23.
Tumor-associated macrophages (TAMs) can have protumor properties, including suppressing immune responses, promoting vascularization and, consequently, augmenting tumor progression. To stop TAM-mediated immunosuppression, we use a novel treatment by injecting antibodies specific for scavenger receptor MARCO, which is expressed on a specific subpopulation of TAMs in the tumor. We now report the location of this TAM as well as the pleiotropic mechanism of action of anti-MARCO antibody treatment on tumor progression and further show that this is potentially relevant to humans. Using specific targeting, we observed decreased tumor vascularization, a switch in the metabolic program of MARCO-expressing macrophages, and activation of natural killer (NK) cell killing through TNF-related apoptosis-inducing ligand (TRAIL). This latter activity reverses the effect of melanoma cell-conditioned macrophages in blocking NK activation and synergizes with T cell-directed immunotherapy, such as antibodies to PD-1 or PD-L1, to enhance tumor killing. Our study thus reveals an approach to targeting the immunosuppressive tumor microenvironment with monoclonal antibodies to enhance NK cell activation and NK cell-mediated killing. This can complement existing T cell-directed immunotherapy, providing a promising approach to combinatorial immunotherapy for cancer.
肿瘤相关巨噬细胞（TAMs）具有促肿瘤特性，包括抑制免疫反应、促进血管生成，从而促进肿瘤进展。为了阻止 TAM 介导的免疫抑制，我们采用了一种新的治疗方法，即注射针对清道夫受体 MARCO 的抗体，该受体在肿瘤中特定的 TAM 亚群上表达。我们现在报告了这种 TAM 的位置以及抗 MARCO 抗体治疗对肿瘤进展的多效性作用机制，并进一步表明这可能与人类有关。通过特异性靶向，我们观察到肿瘤血管生成减少，MARCO 表达的巨噬细胞代谢程序发生转变，以及通过 TNF 相关凋亡诱导配体（TRAIL）激活自然杀伤（NK）细胞杀伤。后一种活性逆转了黑色素瘤细胞条件培养基巨噬细胞阻断 NK 激活的作用，并与针对 PD-1 或 PD-L1 的 T 细胞导向免疫疗法协同作用，增强肿瘤杀伤。因此，我们的研究揭示了一种使用单克隆抗体靶向免疫抑制性肿瘤微环境的方法，以增强 NK 细胞的激活和 NK 细胞介导的杀伤。这可以补充现有的 T 细胞导向免疫疗法，为癌症的组合免疫疗法提供一种有前途的方法。
