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Updated: Aug 9, 2025
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death
Tove Selvin1, Malin Berglund2, Lena Lenhammar2
1Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-75185, Uppsala, Sweden. tove.selvin@medsci.uu.se.
Background:
High-throughput screening (HTS) of small molecule drug libraries has greatly facilitated the discovery of new cancer drugs. However, most phenotypic screening platforms used in the field of oncology are based solely on cancer cell populations and do not allow for the identification of immunomodulatory agents.
Methods:
We developed a phenotypic screening platform based on a miniaturized co-culture system with human colorectal cancer- and immune cells, providing a model that recapitulates part of the tumor immune microenvironment (TIME) complexity while simultaneously being compatible with a simple image-based readout. Using this platform, we screened 1,280 small molecule drugs, all approved by the Food and Drug Administration (FDA), and identified statins as enhancers of immune cell-induced cancer cell death.
Results:
The lipophilic statin pitavastatin had the most potent anti-cancer effect. Further analysis demonstrated that pitavastatin treatment induced a pro-inflammatory cytokine profile as well as an overall pro-inflammatory gene expression profile in our tumor-immune model.
Conclusion:
Our study provides an in vitro phenotypic screening approach for the identification of immunomodulatory agents and thus addresses a critical gap in the field of immuno-oncology. Our pilot screen identified statins, a drug family gaining increasing interest as repurposing candidates for cancer treatment, as enhancers of immune cell-induced cancer cell death. We speculate that the clinical benefits described for cancer patients receiving statins are not simply caused by a direct effect on the cancer cells but rather are dependent on the combined effect exerted on both cancer and immune cells.
Insights
This study introduces a new screening method to find cancer drugs that boost immune responses. Statins were identified as drugs that enhance immune cell-driven cancer cell death, offering new avenues for immuno-oncology drug discovery.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- High-throughput screening (HTS) aids cancer drug discovery but often overlooks immunomodulatory agents.
- Current phenotypic screening platforms in oncology primarily focus on cancer cells, neglecting immune cell interactions.
- A gap exists in identifying drugs that modulate the tumor immune microenvironment (TIME).
Purpose of the Study:
- To develop a novel phenotypic screening platform for identifying immunomodulatory agents.
- To screen FDA-approved small molecule drugs for their effect on cancer-immune cell interactions.
- To address the limitations of current screening methods in immuno-oncology.
Main Methods:
- Developed a miniaturized co-culture system using human colorectal cancer and immune cells.
- Implemented a simple image-based readout compatible with high-throughput screening.
- Screened 1,280 FDA-approved small molecule drugs using the developed platform.
Main Results:
- Identified statins as a class of drugs that enhance immune cell-induced cancer cell death.
- The lipophilic statin pitavastatin demonstrated the most potent anti-cancer effect in the model.
- Pitavastatin treatment induced a pro-inflammatory cytokine and gene expression profile in the tumor-immune model.
Conclusions:
- The developed platform offers an in vitro approach for identifying immunomodulatory agents, filling a critical gap in immuno-oncology.
- Statins show potential as repurposing candidates for cancer treatment by enhancing immune-mediated cancer cell death.
- Clinical benefits of statins in cancer patients may stem from their combined effects on both cancer and immune cells, not just direct anti-cancer activity.
