Losartan Rewires the Tumor-immune Microenvironment and Suppresses IGF-1 to Overcome Resistance to Chemo-immunotherapy in Ovarian Cancer

Overview

Journal Br J Cancer

Specialty Oncology

Date 2024 Oct 5

PMID 39369055

Authors

Yao Sun

Zhenzhen Yin

Shuang Li

Limeng Wu

Yanling Zhang

Yanxia Zhao

Igor L Gomes Dos Santos

Sonu Subudhi

Pinji Lei

Alona Muzikansky

Zhiyong Yuan

Bo R Rueda

Rakesh K Jain

Lei Xu

Affiliations

Soon will be listed here.

Abstract

Background: Ovarian cancer (OvCa) is the most lethal of the gynecologic malignancies. Immune checkpoint inhibitors, which have revolutionized the treatment of multiple malignancies, have had limited efficacy in OvCa patients. This lack of effectiveness is partly due to the abnormal ovarian tumor microenvironment (TME), displaying a desmoplastic, highly fibrotic extracellular matrix. High extracellular matrix deposition leads to a buildup of compressive forces that cause tumor blood vessel collapse, reduced vessel perfusion, poor delivery of drugs, and compromised trafficking of cytotoxic T-cells to these tumors.

Methods: Using two syngeneic OvCa models, we tested the effect of losartan, a widely prescribed anti-hypertensive drug, on reprogramming the TME and chemosensitizing the cancer cells.

Results: Losartan treatment (i) reprograms the TME leading to increased vascular perfusion, and thus enhances drug delivery and immune effector cell intratumoral infiltration and function; and (ii) rewires the OvCa cells by suppressing the IGF-1 signaling, resulting in enhanced chemosensitivity. As a result of the combined tumor and stromal effects, losartan treatment enhances the efficacy of chemo-immunotherapy in OvCa models.

Conclusion: The safety and low cost ( < $1-2/day) of losartan warrant rapid translation of our findings to patients with OvCa.

References

Fukumura D, Kloepper J, Amoozgar Z, Duda D, Jain R . Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018; 15(5):325-340. PMC: 5921900. DOI: 10.1038/nrclinonc.2018.29. View

Pinter M, Jain R . Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy. Sci Transl Med. 2017; 9(410). PMC: 5928511. DOI: 10.1126/scitranslmed.aan5616. View

Maniati E, Berlato C, Gopinathan G, Heath O, Kotantaki P, Lakhani A . Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment. Cell Rep. 2020; 30(2):525-540.e7. PMC: 6963791. DOI: 10.1016/j.celrep.2019.12.034. View

Jain R, Martin J, Stylianopoulos T . The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng. 2014; 16:321-46. PMC: 4109025. DOI: 10.1146/annurev-bioeng-071813-105259. View

Regan D, Chow L, Das S, Haines L, Palmer E, Kurihara J . Losartan Blocks Osteosarcoma-Elicited Monocyte Recruitment, and Combined With the Kinase Inhibitor Toceranib, Exerts Significant Clinical Benefit in Canine Metastatic Osteosarcoma. Clin Cancer Res. 2021; 28(4):662-676. PMC: 8866227. DOI: 10.1158/1078-0432.CCR-21-2105. View

Zhdanov D, Gladilina Y, Pokrovsky V, Grishin D, Grachev V, Orlova V . Murine regulatory T cells induce death of effector T, B, and NK lymphocytes through a contact-independent mechanism involving telomerase suppression and telomere-associated senescence. Cell Immunol. 2018; 331:146-160. DOI: 10.1016/j.cellimm.2018.06.008. View

Alemi Yahya M, Meisel Sharon S, Hantisteanu S, Hallak M, Bruchim I . The Role of the Insulin-Like Growth Factor 1 Pathway in Immune Tumor Microenvironment and Its Clinical Ramifications in Gynecologic Malignancies. Front Endocrinol (Lausanne). 2018; 9:297. PMC: 5996273. DOI: 10.3389/fendo.2018.00297. View

Mamay C, Mingo-Sion A, Wolf D, Molina M, Van Den Berg C . An inhibitory function for JNK in the regulation of IGF-I signaling in breast cancer. Oncogene. 2003; 22(4):602-14. DOI: 10.1038/sj.onc.1206186. View

Zhao Y, Cao J, Melamed A, Worley M, Gockley A, Jones D . Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. Proc Natl Acad Sci U S A. 2019; 116(6):2210-2219. PMC: 6369817. DOI: 10.1073/pnas.1818357116. View

10.

Gubin M, Zhang X, Schuster H, Caron E, Ward J, Noguchi T . Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014; 515(7528):577-81. PMC: 4279952. DOI: 10.1038/nature13988. View

11.

Matulonis U, Shapira-Frommer R, Santin A, Lisyanskaya A, Pignata S, Vergote I . Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019; 30(7):1080-1087. DOI: 10.1093/annonc/mdz135. View

12.

Huang Y, Yuan J, Righi E, Kamoun W, Ancukiewicz M, Nezivar J . Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012; 109(43):17561-6. PMC: 3491458. DOI: 10.1073/pnas.1215397109. View

13.

Li T, Forbes M, Fuller G, Li J, Yang X, Zhang W . IGFBP2: integrative hub of developmental and oncogenic signaling network. Oncogene. 2020; 39(11):2243-2257. PMC: 7347283. DOI: 10.1038/s41388-020-1154-2. View

14.

Samrao D, Wang D, Ough F, Lin Y, Liu S, Menesses T . Histologic parameters predictive of disease outcome in women with advanced stage ovarian carcinoma treated with neoadjuvant chemotherapy. Transl Oncol. 2013; 5(6):469-74. PMC: 3567723. DOI: 10.1593/tlo.12265. View

15.

Yee D, Morales F, Hamilton T, Von Hoff D . Expression of insulin-like growth factor I, its binding proteins, and its receptor in ovarian cancer. Cancer Res. 1991; 51(19):5107-12. View

16.

Baron-Hay S, Boyle F, Ferrier A, Scott C . Elevated serum insulin-like growth factor binding protein-2 as a prognostic marker in patients with ovarian cancer. Clin Cancer Res. 2004; 10(5):1796-806. DOI: 10.1158/1078-0432.ccr-0672-2. View

17.

Carstens J, Correa de Sampaio P, Yang D, Barua S, Wang H, Rao A . Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat Commun. 2017; 8:15095. PMC: 5414182. DOI: 10.1038/ncomms15095. View

18.

Roby K, TAYLOR C, Sweetwood J, Cheng Y, Pace J, Tawfik O . Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis. 2000; 21(4):585-91. DOI: 10.1093/carcin/21.4.585. View

19.

Stylianopoulos T, Munn L, Jain R . Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside. Trends Cancer. 2018; 4(4):292-319. PMC: 5930008. DOI: 10.1016/j.trecan.2018.02.005. View

20.

Remsing Rix L, Sumi N, Hu Q, Desai B, Bryant A, Li X . IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells. Sci Signal. 2022; 15(747):eabj5879. PMC: 9528501. DOI: 10.1126/scisignal.abj5879. View