Research Article

Low-dose metronomic gemcitabine pretreatments overcome the resistance of breast cancer to immune checkpoint therapy

Xichen Zheng‡

Jiajie Kuai‡

Guanghui Shen

Xichen Zheng‡

*Author for correspondence: Tel.: +86 188 9651 6375;

E-mail Address: xczheng@fudan.edu.cn

https://orcid.org/0000-0002-9868-4396

Institute of Pediatrics, Children’s Hospital of Fudan University, Shanghai, 200000, China

‡Authors contributed equally

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Jiajie Kuai‡

https://orcid.org/0000-0001-9715-3975

Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory & Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory & Immune Medicine, Anhui Medical University, Hefei, 230000, China

Cyrus Tang Hematology Center of Soochow University, Suzhou, 215000, China

‡Authors contributed equally

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Guanghui Shen

https://orcid.org/0000-0003-2887-436X

Institute of Pediatrics, Children’s Hospital of Fudan University, Shanghai, 200000, China

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Published Online:7 Mar 2023https://doi.org/10.2217/imt-2022-0254

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Abstract

Aims: Immunotherapy has revolutionized cancer management. However, response to immunotherapy is heterogeneous. Thus, strategies to improve antitumor immune responses in resistant tumors, such as breast cancer, are urgently needed. Methods: Established murine tumors were treated with anti-CTLA4 or anti-PD-1 alone or combined with metronomic gemcitabine (met-GEM). Tumor vascular function, immune cell tumor infiltration and gene transcription were determined. Results: Low-dose met-GEM (2 mg/kg) treatments improved tumor vessel perfusion and increased tumor-infiltrating T cells. Notably, low-dose met-GEM pretreatments converted resistant tumors to respond to immunotherapy. Moreover, combined therapy reduced tumor vessel density, improved tumor vessel perfusion, increased T-cell tumor infiltration and upregulated the expression of some anticancer genes. Conclusion: Low-dose met-GEM pretreatment reconditioned the tumor immune microenvironment and improved immunotherapy efficacy in murine breast cancer.

Plain language summary

Breast cancer is the most commonly diagnosed cancer in women globally. However, only a small subset of breast cancer patients benefits from treatment with immunotherapy. Thus, strategies aiming to enhance the antitumor effects of immunotherapies in breast cancer are an urgent requirement. We found that low-dose metronomic gemcitabine treatments improved tumor vessel function and increased tumor-infiltrating T cells, and did not deplete myeloid-derived suppressor cells, but did not affect tumor growth in the murine breast cancer model. Notably, however, low-dose metronomic gemcitabine pretreatments sensitized breast cancers to immunotherapy. Our findings provide important insights into the optimal strategies for combining immunotherapy with improved tumor vessel perfusion.

Tweetable abstract

Low-dose metronomic gemcitabine (met-GEM) improves tumor vessel perfusion and increases tumor-infiltrating T cells. Pretreatment with low-dose met-GEM sensitizes resistant breast cancers to immunotherapy.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 15, No. 6

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Received 8 October 2022

Accepted 23 February 2023

Published online 7 March 2023

Published in print April 2023

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/imt-2022-0254

Author contributions

X Zheng designed the study; X Zheng and J Kuai performed the experiments; G Shen provided essential reagents; X Zheng drafted the manuscript.

Acknowledgments

The authors are grateful to Y Huang (Soochow University) for technical support.

Financial & competing interests disclosure

This study was supported by the National Natural Science Foundation of China (grant no. 81903167) and the Shanghai Sailing Program (grant no. 19YF1403900). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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