肿瘤相关巨噬细胞（TAM）是肿瘤环境的主要组成部分，它们的积聚往往与预后不良相关，通过导致局部炎症、抑制抗肿瘤免疫反应和耐抗癌治疗做出贡献。因此，在本研究中，我们调查了以化学炎症受体ChemR23作为靶点，使用一种激动剂单克隆抗体αChemR23来治疗癌症的疗效。我们通过利用人类GM-CSF、M-CSF和肿瘤相关巨噬细胞（TAM-like）分化的巨噬细胞分别通过与GM-CSF、M-CSF或肿瘤细胞上清液（乳腺癌（BC）或恶性胸膜间皮瘤（MPM）细胞）孵育来获得。我们在转录组、蛋白质和功能水平上研究了αChemR23对巨噬细胞的影响。我们使用The Cancer Genome Atlas（TCGA）的数据集研究了BC和MPM肿瘤中编码ChemR23的CMKLR1表达。在体内，我们评估了αChemR23对总体存活率、转移发展和转移灶转录组改变的影响，使用了切除的三阴性乳腺癌模型。我们发现在M-CSF和肿瘤细胞上清液分化的巨噬细胞（TAM-like）中，ChemR23的表达水平高于GM-CSF分化的巨噬细胞。αChemR23引起的ChemR23激活在M-CSF和TAM-like巨噬细胞中深度调节了细胞表面标记物、细胞因子分泌、基因mRNA表达和免疫功能。ChemR23编码基因（CMKLR1）的表达与人类BC肿瘤和MPM的TAM标记物强相关，其在这些肿瘤中的组织学检测主要对应TAM表达。在体内，治疗使用αChemR23激动剂增加了小鼠的生存率，并降低了三阴性乳腺癌转移的发生率，与转移灶中TAM表型的调节相对应。这些结果为通过ChemR23靶向TAM和炎症调节来避免TAM的促肿瘤效应提供了有吸引力的机会。版权所有©2023 Lavy，Gauttier，Dumont，Chocteau，Deshayes，Fresquet，Dehame，Girault，Trilleaud，Neyton，Mary，Juin，Poirier，Barillé-Nion and Blanquart.

Tumor Associated Macrophages (TAM) are a major component of the tumor environment and their accumulation often correlates with poor prognosis by contributing to local inflammation, inhibition of anti-tumor immune response and resistance to anticancer treatments. In this study, we thus investigated the anti-cancer therapeutic interest to target ChemR23, a receptor of the resolution of inflammation expressed by macrophages, using an agonist monoclonal antibody, αChemR23.Human GM-CSF, M-CSF and Tumor Associated Macrophage (TAM)-like macrophages were obtained by incubation of monocytes from healthy donors with GM-CSF, M-CSF or tumor cell supernatants (Breast cancer (BC) or malignant pleural mesothelioma (MPM) cells). The effects of αChemR23 on macrophages were studied at the transcriptomic, protein and functional level. Datasets from The Cancer Genome Atlas (TCGA) were used to study CMKLR1 expression, coding for ChemR23, in BC and MPM tumors. In vivo, αChemR23 was evaluated on overall survival, metastasis development and transcriptomic modification of the metastatic niche using a model of resected triple negative breast cancer.We show that ChemR23 is expressed at higher levels in M-CSF and tumor cell supernatant differentiated macrophages (TAM-like) than in GM-CSF-differentiated macrophages. ChemR23 activation triggered by αChemR23 deeply modulates M-CSF and TAM-like macrophages including profile of cell surface markers, cytokine secretion, gene mRNA expression and immune functions. The expression of ChemR23 coding gene (CMKLR1) strongly correlates to TAM markers in human BC tumors and MPM and its histological detection in these tumors mainly corresponds to TAM expression. In vivo, treatment with αChemR23 agonist increased mouse survival and decreased metastasis occurrence in a model of triple-negative BC in correlation with modulation of TAM phenotype in the metastatic niche.These results open an attractive opportunity to target TAM and the resolution of inflammation pathways through ChemR23 to circumvent TAM pro-tumoral effects.Copyright © 2023 Lavy, Gauttier, Dumont, Chocteau, Deshayes, Fresquet, Dehame, Girault, Trilleaud, Neyton, Mary, Juin, Poirier, Barillé-Nion and Blanquart.