Weich Adrian, Berges Johannes, Flamann Cindy, Bitterer Katrin, Singh Krishna Pal, Chambers David, Lischer Christopher, Lai Xin, Wolkenhauer Olaf, Berking Carola, Krönke Gerhard, Gupta Shailendra, Bruns Heiko, Vera Julio, Macrophages Research Group
Department of Dermatology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum Erlangen, 91054, Erlangen, Germany.
Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054, Erlangen, Germany.
J Exp Clin Cancer Res. 2025 Aug 4;44(1):225. doi: 10.1186/s13046-025-03478-5.
The metastatic microenvironment is often rich in tumor-associated macrophages (TAMs). In uveal melanoma (UM), high levels of TAMs positively correlate with tumor progression and poorer prognosis. We hypothesize that the immunomodulation of TAMs can remodel the UM tumor microenvironment and make it more susceptible to therapeutic interventions.
In our work, we designed a novel computational pipeline that combines single-cell transcriptomics data, network analysis, multicriteria decision techniques, and pharmacophore-based docking simulations to select molecular targets and matching repurposable drugs for TAM immunomodulation. The method generates a ranking of drug-target interactions, the most promising of which are channeled towards experimental validation.
To identify potential immunomodulatory targets, we created a network-based representation of the TAM interactome and extracted a regulatory core conditioned on UM expression data. Further, we selected 13 genes from this core (NLRP3, HMOX1, CASP1, GSTP1, NAMPT, HSP90AA1, B2M, ISG15, LTA4H, PTGS2, CXCL2, PLAUR, ZFP36, TANK) for pharmacophore-based virtual screening of FDA-approved compounds, followed by flexible molecular docking. Based on the ranked docking results, we chose the interaction between caspase-1 and clindamycin for experimental validation. Functional studies on macrophages confirmed that clindamycin inhibits caspase-1 activity and thereby inflammasome activation, leading to a decrease in IL-1β, IL-18, and gasdermin D cleavage products as well as a reduction in pyroptotic cell death. This clindamycin-mediated inhibition of caspase-1 was also observable in TAMs derived from the bone marrow of multiple myeloma patients.
Our computational workflow for drug repurposing identified clindamycin as an efficacious inhibitor of caspase-1 that suppresses inflammasome activity and pyroptosis in vitro in TAMs.
转移性微环境中通常富含肿瘤相关巨噬细胞（TAM）。在葡萄膜黑色素瘤（UM）中，高水平的TAM与肿瘤进展和较差的预后呈正相关。我们假设对TAM进行免疫调节可以重塑UM肿瘤微环境，使其更容易受到治疗干预。
在我们的研究中，我们设计了一种新颖的计算流程，该流程结合单细胞转录组学数据、网络分析、多标准决策技术和基于药效团的对接模拟，以选择用于TAM免疫调节的分子靶点和匹配的可重新利用药物。该方法生成药物-靶点相互作用的排名，其中最有前景的相互作用将用于实验验证。
为了识别潜在的免疫调节靶点，我们创建了基于网络的TAM相互作用组表示，并根据UM表达数据提取了一个调节核心。此外，我们从该核心中选择了13个基因（NLRP3、HMOX1、CASP1、GSTP1、NAMPT、HSP90AA1、B2M、ISG15、LTA4H、PTGS2、CXCL2、PLAUR、ZFP36、TANK），用于对FDA批准的化合物进行基于药效团的虚拟筛选，随后进行柔性分子对接。基于对接结果的排名，我们选择了半胱天冬酶-1与克林霉素之间的相互作用进行实验验证。对巨噬细胞的功能研究证实，克林霉素抑制半胱天冬酶-1的活性，从而抑制炎性小体的激活，导致IL-1β、IL-18和gasdermin D裂解产物减少，以及焦亡细胞死亡减少。在源自多发性骨髓瘤患者骨髓的TAM中也可观察到克林霉素介导的对半胱天冬酶-1的抑制作用。
我们用于药物重新利用的计算工作流程确定克林霉素是一种有效的半胱天冬酶-1抑制剂，可在体外抑制TAM中的炎性小体活性和焦亡。
