Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death
Abstract 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 identificati...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-02-01
|
| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-023-10645-4 |
| _version_ | 1827983862767026176 |
|---|---|
| author | Tove Selvin Malin Berglund Lena Lenhammar Malin Jarvius Peter Nygren Mårten Fryknäs Rolf Larsson Claes R Andersson |
| author_facet | Tove Selvin Malin Berglund Lena Lenhammar Malin Jarvius Peter Nygren Mårten Fryknäs Rolf Larsson Claes R Andersson |
| author_sort | Tove Selvin |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-09T22:52:52Z |
| format | Article |
| id | doaj.art-6a001318eb47461bbdbb33b4e9a1a25b |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-09T22:52:52Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-6a001318eb47461bbdbb33b4e9a1a25b2023-03-22T11:34:35ZengBMCBMC Cancer1471-24072023-02-0123111010.1186/s12885-023-10645-4Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell deathTove Selvin0Malin Berglund1Lena Lenhammar2Malin Jarvius3Peter Nygren4Mårten Fryknäs5Rolf Larsson6Claes R Andersson7Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala UniversityDepartment of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala UniversityDepartment of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala UniversityDepartment of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala UniversityDepartment of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala UniversityDepartment of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala UniversityAbstract 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.https://doi.org/10.1186/s12885-023-10645-4Immuno-oncologyDrug screeningRepurposingSmall molecule drugsStatins |
| spellingShingle | Tove Selvin Malin Berglund Lena Lenhammar Malin Jarvius Peter Nygren Mårten Fryknäs Rolf Larsson Claes R Andersson Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death BMC Cancer Immuno-oncology Drug screening Repurposing Small molecule drugs Statins |
| title | Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death |
| title_full | Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death |
| title_fullStr | Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death |
| title_full_unstemmed | Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death |
| title_short | Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death |
| title_sort | phenotypic screening platform identifies statins as enhancers of immune cell induced cancer cell death |
| topic | Immuno-oncology Drug screening Repurposing Small molecule drugs Statins |
| url | https://doi.org/10.1186/s12885-023-10645-4 |
| work_keys_str_mv | AT toveselvin phenotypicscreeningplatformidentifiesstatinsasenhancersofimmunecellinducedcancercelldeath AT malinberglund phenotypicscreeningplatformidentifiesstatinsasenhancersofimmunecellinducedcancercelldeath AT lenalenhammar phenotypicscreeningplatformidentifiesstatinsasenhancersofimmunecellinducedcancercelldeath AT malinjarvius phenotypicscreeningplatformidentifiesstatinsasenhancersofimmunecellinducedcancercelldeath AT peternygren phenotypicscreeningplatformidentifiesstatinsasenhancersofimmunecellinducedcancercelldeath AT martenfryknas phenotypicscreeningplatformidentifiesstatinsasenhancersofimmunecellinducedcancercelldeath AT rolflarsson phenotypicscreeningplatformidentifiesstatinsasenhancersofimmunecellinducedcancercelldeath AT claesrandersson phenotypicscreeningplatformidentifiesstatinsasenhancersofimmunecellinducedcancercelldeath |