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Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1
Adrian Weich1,2,3, Johannes Berges4, Cindy Flamann4
1Department of Dermatology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum Erlangen, 91054, Erlangen, Germany.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
This study identifies clindamycin as a drug that can modulate tumor-associated macrophages (TAMs) by inhibiting caspase-1. This finding offers a new therapeutic strategy for uveal melanoma (UM) by reducing tumor progression.
Area of Science:
- Oncology
- Immunology
- Computational Biology
Background:
- Tumor-associated macrophages (TAMs) are prevalent in the metastatic microenvironment and linked to uveal melanoma (UM) progression.
- High TAM levels correlate with poorer prognosis in UM patients.
- Modulating TAMs may remodel the UM tumor microenvironment for enhanced therapeutic efficacy.
Purpose of the Study:
- To identify novel therapeutic targets and repurposable drugs for TAM immunomodulation in UM.
- To computationally predict drug-target interactions for suppressing TAM-driven tumor progression.
- To validate computational predictions through experimental functional studies.
Main Methods:
- Developed a computational pipeline integrating single-cell transcriptomics, network analysis, multicriteria decision techniques, and pharmacophore docking.
- Constructed a TAM interactome network and identified a regulatory core from UM expression data.
- Screened FDA-approved compounds against 13 selected genes, prioritizing clindamycin for its interaction with caspase-1.
Main Results:
- Clindamycin was identified as a potent inhibitor of caspase-1 activity in macrophages.
- Clindamycin suppressed inflammasome activation, reducing IL-1β, IL-18, and gasdermin D cleavage products.
- Inhibition of pyroptotic cell death by clindamycin was confirmed in TAMs from UM and multiple myeloma models.
Conclusions:
- A computational drug repurposing workflow successfully identified clindamycin as an effective inhibitor of caspase-1.
- Clindamycin suppresses inflammasome activity and pyroptosis in TAMs in vitro.
- This approach provides a promising strategy for targeting TAMs in uveal melanoma and potentially other cancers.
