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Translational Therapeutics

Losartan rewires the tumor-immune microenvironment and suppresses IGF-1 to overcome resistance to chemo-immunotherapy in ovarian cancer

British Journal of Cancer volume 131, pages 1683–1693 (2024)Cite this article

Subjects

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.

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Fig. 1: Losartan treatment reprograms the TME from immunosuppressive to immunostimulatory in OvCa models.
Fig. 2: Combined losartan treatment improves chemo-immunotherapy efficacy in OvCa models.
Fig. 3: Losartan treatment enhances αPD1 efficacy, via increasing intratumoral drug delivery and immune effector cell infiltration in mouse OvCa models.
Fig. 4: Losartan treatment suppresses IGF signaling in the OvCa model.
Fig. 5: Losartan treatment, via suppressing the IGF-1 signaling, enhances chemo-immunotherapy.
Fig. 6: Losartan treatment is associated with reduced matrix level, fibrogenic signaling, and increased immune cell infiltration in OvCa patients.

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Data availability

The data generated in this study are available upon request from the corresponding author.

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Acknowledgements

We thank Dr. Brian Seed for providing the cloning vector, we thank Mark Duquette, Naifang Lu, and Anna Khachatryan for their superb technical support, and Dr. Peigen Huang for assisting in animal studies.

Funding

This study was supported by the American Cancer Society Mission Boost Award (to L.X.), NIH R01-NS126187 and R01-DC020724 (to L.X.), Department of Defense Investigator-Initiated Research Award (W81XWH-20-1-0222, to L.X.) and Clinical Trial Award (W81XWH2210439, to L.X.), Children’s Tumor Foundation Drug Discovery Initiative (to L.X.); NIH grant R35-CA197743, and in part through grants R01- R01CA259253, R01-CA269672, R01-NS118929, U01-CA224348 and U01-CA261842 and by Nile Albright Research Foundation, the National Foundation for Cancer Research, Harvard Ludwig Cancer Center, and Jane’s Trust Foundation (to R.K.J.); and Nile Albright Research Foundation, Vincent Memorial Hospital Foundation, NCI P50CA240243, Julie Fund, Worden Family Foundation (to B.R.R).

Author information

Author notes

  1. Yao Sun & Zhiyong Yuan

    Present address: Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Clinical Research for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China

  2. Yanxia Zhao

    Present address: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430023, China

  3. These authors contributed equally: Yao Sun, Zhenzhen Yin.

Authors and Affiliations

  1. Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA

    Yao Sun, Zhenzhen Yin, Shuang Li, Limeng Wu, Yanling Zhang, Yanxia Zhao, Igor L. Gomes dos Santos, Sonu Subudhi, Pinji Lei, Rakesh K. Jain & Lei Xu

  2. Division of Biostatistics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Alona Muzikansky

  3. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430023, China

    Zhiyong Yuan

  4. Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Bo R. Rueda

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Contributions

L.X. designed the research; Y.S., Z.Y., Y.Z. and S.L. performed mouse model studies; Y.S., L.W., S.L. performed histological studies; S.S. and P.L. analyzed RNASeq data; Y.S., L.W., B.R.R., and A.M. performed patient sample analysis; Y.S., Z.Y., L.W., Y.Z., I.L.G., S.S., P.L., A.M. and Z.Y. analyzed data; L.X. and R.K.J. wrote the paper.

Corresponding author

Correspondence to Lei Xu.

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Competing interests

R.K.J. received consultant fees from Cur, Elpis, Innocoll, SPARC, and SynDevRx; owns equity in Accurius, Enlight, and SynDevRx; is on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund; and received research grants from Boehringer Ingelheim and Sanofi. No funding or reagents from these companies were used in this study. B.R.R. reports serving on the advisory board for VincenTech which has no direct connection to the current research. The other authors have no competing interests to declare.

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Sun, Y., Yin, Z., Li, S. et al. Losartan rewires the tumor-immune microenvironment and suppresses IGF-1 to overcome resistance to chemo-immunotherapy in ovarian cancer. Br J Cancer 131, 1683–1693 (2024). https://doi.org/10.1038/s41416-024-02863-9

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