肿瘤相关巨噬细胞 (TAM) 和其他骨髓单核细胞参与调节对免疫疗法的反应，包括针对 PD-1/PD-L1 轴的免疫检查点抑制剂 (ICIs)。我们开发了一种离体高通量方法来发现巨噬细胞介导的 T 细胞抑制调节剂，这可以改善 ICI 的临床结果。我们使用骨髓源性巨噬细胞 (BMDM) 和脾源性 T 细胞进行共培养测定，筛选了 1,430 种美国食品和药物管理局 (FDA) 批准的小分子药物。鉴定出了 57 种可破坏巨噬细胞介导的 T 细胞抑制的化合物。与 αPD-L1 结合时，七种化合物发挥了显着的协同 T 细胞扩增活性。其中包括四种 COX1/2 抑制剂和两种骨髓细胞信号传导抑制剂。我们证明，在三阴性乳腺癌 (TNBC) 肿瘤模型中，环加氧酶 (COX)1/2 抑制剂与 αPD-L1 联合使用可以降低肿瘤生长动力学，并以 CD8 T 细胞依赖性方式提高总体生存率。总之，我们提出了一种合理化的方法来识别与 ICI 协同作用的化合物，以潜在地增强实体瘤患者的治疗效果。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Tumor-associated macrophages (TAMs) and other myelomonocytic cells are implicated in regulating responsiveness to immunotherapies, including immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis. We have developed an ex vivo high-throughput approach to discover modulators of macrophage-mediated T cell suppression, which can improve clinical outcomes of ICIs. We screened 1,430 Food and Drug Administration (FDA)-approved small-molecule drugs using a co-culture assay employing bone-marrow-derived macrophages (BMDMs) and splenic-derived T cells. This identified 57 compounds that disrupted macrophage-mediated T cell suppression. Seven compounds exerted prominent synergistic T cell expansion activity when combined with αPD-L1. These include four COX1/2 inhibitors and two myeloid cell signaling inhibitors. We demonstrate that the use of cyclooxygenase (COX)1/2 inhibitors in combination with αPD-L1 decreases tumor growth kinetics and enhances overall survival in triple-negative breast cancer (TNBC) tumor models in a CD8+ T cell-dependent manner. Altogether, we present a rationalized approach for identifying compounds that synergize with ICI to potentially enhance therapeutic outcomes for patients with solid tumors.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.