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Open Access 01-12-2023 | Statins | Research

Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death

Authors: Tove Selvin, Malin Berglund, Lena Lenhammar, Malin Jarvius, Peter Nygren, Mårten Fryknäs, Rolf Larsson, Claes R Andersson

Published in: BMC Cancer | Issue 1/2023

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.

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Emens LA et al. “Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape,” European Journal of Cancer, vol. 81. Elsevier Ltd, pp. 116–129, Aug. 01, 2017. doi: https://doi.org/10.1016/j.ejca.2017.01.035.

Cheng B, Yuan WE, Su J, Liu Y, Chen J. “Recent advances in small molecule based cancer immunotherapy,” European Journal of Medicinal Chemistry, vol. 157. Elsevier Masson SAS, pp. 582–598, Sep. 05, 2018. doi: https://doi.org/10.1016/j.ejmech.2018.08.028.

Coussens NP, Braisted JC, Peryea T, Sittampalam GS, Simeonov A, Hall MD. “Small-molecule screens: A gateway to cancer therapeutic agents with case studies of food and drug administration–approved drugs,” Pharmacol Rev, vol. 69, no. 4, pp. 479–496, Oct. 2017, doi: https://doi.org/10.1124/pr.117.013755.

Mo X, Tang C, Niu Q, Ma T, Du Y, Fu H. HTiP: high-throughput Immunomodulator phenotypic screening platform to reveal IAP antagonists as anti-cancer Immune Enhancers. Cell Chem Biol. Mar. 2019;26(3):331–339e. https://doi.org/10.1016/j.chembiol.2018.11.011.

Golshani G, Zhang Y. “Advances in immunotherapy for colorectal cancer: a review,” Therapeutic Advances in Gastroenterology, vol. 13. SAGE Publications Ltd, 2020. doi: https://doi.org/10.1177/1756284820917527.

Meng M, Zhong K, Jiang T, Liu Z, Kwan HY, Su T. The current understanding on the impact of KRAS on colorectal cancer. Biomed Pharmacotherapy. 2021;140. https://doi.org/10.1016/j.biopha.2021.111717. Elsevier Masson s.r.l.

Mullen PJ, Yu R, Longo J, Archer MC, Penn LZ. “The interplay between cell signalling and the mevalonate pathway in cancer,” Nature Reviews Cancer, vol. 16, no. 11. Nature Publishing Group, pp. 718–731, Oct. 24, 2016. doi: https://doi.org/10.1038/nrc.2016.76.

Alizadeh J et al. “Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells,” Sci Rep, vol. 7, Mar. 2017, doi: https://doi.org/10.1038/srep44841.

Jiang P et al. “In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells,” Br J Cancer, vol. 111, no. 8, pp. 1562–1571, Oct. 2014, doi: https://doi.org/10.1038/bjc.2014.431.

10.

Xue L, et al. Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy. Front Oncol. 2020;10. https://doi.org/10.3389/fonc.2020.01510. Frontiers Media S.A.

11.

Ren Q-W, Yu S-Y, Teng T-HK, Li X. “Statin associated lower cancer risk and related mortality in patients with heart failure,” Eur Heart J, vol. 42, no. 32, pp. 3060–3062, Aug. 2021, doi: https://doi.org/10.1093/eurheartj/ehab482.

12.

Zhang Y et al. “Statin Use and Risk of Pancreatic Cancer: An Updated Meta-analysis of 26 Studies,” Pancreas, vol. 48, no. 2. Lippincott Williams and Wilkins, pp. 142–150, Feb. 01, 2019. doi: https://doi.org/10.1097/MPA.0000000000001226.

13.

Kotti A, Holmqvist A, Albertsson M, Sun XF. “Survival benefit of statins in older patients with rectal cancer: A Swedish population-based cohort study,” J Geriatr Oncol, vol. 10, no. 5, pp. 690–697, Sep. 2019, doi: https://doi.org/10.1016/j.jgo.2019.01.011.

14.

Zhang Y, Chen H, Chen S, Li Z, Chen J, Li W. The effect of concomitant use of statins, NSAIDs, low-dose aspirin, metformin and beta-blockers on outcomes in patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis. Oncoimmunology. Jan. 2021;10(1):1957605. https://doi.org/10.1080/2162402x.2021.1957605.

15.

Rossi A, et al. Statins and immunotherapy: togetherness makes strength the potential effect of statins on immunotherapy for NSCLC. Cancer Rep. Aug. 2021;4(4). https://doi.org/10.1002/cnr2.1368.

16.

Omori M, Okuma Y, Hakozaki T, Hosomi Y. “Statins improve survival in patients previously treated with nivolumab for advanced nonsmall cell lung cancer: An observational study,” Mol Clin Oncol, Nov. 2018, doi: https://doi.org/10.3892/mco.2018.1765.

17.

Cantini L, et al. High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients. Eur J Cancer. Feb. 2021;144:41–8. https://doi.org/10.1016/j.ejca.2020.10.031.

18.

Zhang J-H, Chung TDY, Oldenburg KR. “A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays,”J Biomol Screen, vol. 4, no. 2, 1999.

19.

Berenbaum MC. “What is Synergy?,”Pharmalogical Reviws, no.41, 1989.

20.

Henriksbo BD, Schertzer JD. “Is immunity a mechanism contributing to statin-induced diabetes?,” Adipocyte, vol. 4, no. 4. Taylor and Francis Inc., pp. 232–238, Jan. 01, 2015. doi: https://doi.org/10.1080/21623945.2015.1024394.

21.

Lindholm MW, Nilsson J. Simvastatin stimulates macrophage interleukin-1β secretion through an isoprenylation-dependent mechanism. Vascul Pharmacol. Feb. 2007;46(2):91–6. https://doi.org/10.1016/j.vph.2006.07.001.

22.

Perucha E, et al. The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nat Commun. Dec. 2019;10(1). https://doi.org/10.1038/s41467-019-08332-9.

23.

Subramanian A, et al. A Next Generation Connectivity Map: L1000 platform and the first 1,000,000 profiles. Cell. Nov. 2017;171(6):1437–1452e. https://doi.org/10.1016/j.cell.2017.10.049.

24.

Iorio F et al. “Discovery of drug mode of action and drug repositioning from transcriptional responses”, doi: https://doi.org/10.1073/pnas.1000138107/-/DCSupplemental.

25.

Kuang YL, Theusch E, Krauss RM, Medina MW. Identifying genetic modulators of statin response using subject-derived lymphoblastoid cell lines. Pharmacogenomics. May 2021;22(7):413–21. https://doi.org/10.2217/pgs-2020-0197.

26.

Basnet S, Sharma S, Costea DE, Sapkota D. “Expression profile and functional role of S100A14 in human cancer,” 2019. [Online]. Available: www.oncotarget.com

27.

“Lovastatin induced Kruppel like factor 2 (KLF2.), Kruppel like factor 6 (KLF6) and Ras homolog family member B (RHOB) genes and preferentially led to viability reduction of Cisplatinresistant cells Koi 2017”.

28.

Xia Y, et al. The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery. Cell. Nov. 2018;175(4):1059–73. https://doi.org/10.1016/j.cell.2018.08.070. .e21.

29.

Williams IR. “CCR6 and CCL20: partners in intestinal immunity and lymphorganogenesis. ” in Annals of the New York Academy of Sciences. 2006;1072:52–61. https://doi.org/10.1196/annals.1326.036.CrossRef

30.

Ansari AM et al. “Cellular GFP Toxicity and Immunogenicity: Potential Confounders in in Vivo Cell Tracking Experiments,” Stem Cell Reviews and Reports, vol. 12, no. 5. Humana Press Inc., pp. 553–559, Oct. 01, 2016. doi: https://doi.org/10.1007/s12015-016-9670-8.

31.

Jiang W, Hu JW, He XR, Jin WL, He XY. “Statins: a repurposed drug to fight cancer,” Journal of Experimental and Clinical Cancer Research, vol. 40, no. 1. BioMed Central Ltd, Dec. 01, 2021. doi: https://doi.org/10.1186/s13046-021-02041-2.

32.

Jain MK, Ridker PM. “Anti-inflammatory effects of statins: Clinical evidence and basic mechanisms,” Nature Reviews Drug Discovery, vol. 4, no. 12. pp. 977–987, Dec. 2005. doi: https://doi.org/10.1038/nrd1901.

33.

Perez-Ruiz E, et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature. May 2019;569(7756):428–32. https://doi.org/10.1038/s41586-019-1162-y.

34.

Bertrand F, et al. TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat Commun. Dec. 2017;8(1). https://doi.org/10.1038/s41467-017-02358-7.

35.

Frazzi R. “BIRC3 and BIRC5: multi-faceted inhibitors in cancer,” Cell and Bioscience, vol. 11, no. 1. BioMed Central Ltd, Dec. 01, 2021. doi: https://doi.org/10.1186/s13578-020-00521-0.

36.

Estornes Y, Bertrand MJM. “IAPs, regulators of innate immunity and inflammation,” Seminars in Cell and Developmental Biology, Vol. 39.Elsevier Ltd,pp. 106–114, Mar. 01, 2015. doi: https://doi.org/10.1016/j.semcdb.2014.03.035.

37.

Nam GH, et al. Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer. J Immunother Cancer. Jul. 2021;9(7). https://doi.org/10.1136/jitc-2021-002474.

38.

Liu J, et al. Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients. J Transl Med. Dec. 2021;19(1). https://doi.org/10.1186/s12967-020-02638-9.

39.

Björkhem-Bergman L, Lindh JD, Bergman P. What is a relevant statin concentration in cell experiments claiming pleiotropic effects? Br J Clin Pharmacol. Jul. 2011;72:164–5. https://doi.org/10.1111/j.1365-2125.2011.03907.x.

40.

Catapano AL. “Pitavastatin – pharmacological profile from early phase studies,” 2010.

41.

Beckwitt CH, Brufsky A, Oltvai ZN, Wells A. “Statin drugs to reduce breast cancer recurrence and mortality,” Breast Cancer Research, vol. 20, no. 1. BioMed Central Ltd., Nov. 20, 2018. doi: https://doi.org/10.1186/s13058-018-1066-z.

Title: Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death
Authors: Tove Selvin
Malin Berglund
Lena Lenhammar
Malin Jarvius
Peter Nygren
Mårten Fryknäs
Rolf Larsson
Claes R Andersson
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Statins
Published in: BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-023-10645-4

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