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Complete rejection of large established breast cancer by local immunochemotherapy with T cell activation against neoantigens

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Abstract

Cancer immunotherapies, including immune checkpoint blockage and adoptive transfer of CAR-T cells, have achieved historical successes for many kinds of malignancy. However, a minority of patients survive long term over 5 years without relapse, perhaps owing to tumor heterogeneity and potent immunosuppression in the tumor microenvironment. Here, using an established mouse tumor model of triple-negative 4T1 breast cancer, we show that local immunochemotherapy triggers powerful local and systemic antitumor immunity. Paraneoplastic injection of CpG, α-OX40, and anthracycline completely eliminated both local and distant large established 4T1 breast cancer without obvious relapse. Analysis of the immune cells at tumor tissues, draining lymph nodes, and spleens revealed that the local treatment increased the infiltration of CD4+ and CD8+ T cells in all three tissues and inhibited the accumulation of myeloid-derived suppressor cells in the spleen in a delayed response. Most importantly, this treatment triggered systemic T cell response against 4T1 tumors and some of their neoantigen epitopes as detected by IFN-γ ELISpot and intracellular cytokine assays in splenocytes. Furthermore, T cells showed specific cytotoxic activity against 4T1 tumor cells in vitro. In general, this local immunochemotherapy provides a new approach to target highly diverse neoantigens in various types of cancers without complicated and expensive antigen identification via next-generation sequencing.

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Data availability

Data are available upon reasonable request. All data relevant to the study are included in the paper or uploaded as supplementary material.

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Acknowledgements

We thank Professor Wende Li of Guangzhou Institute of Zoology for gifting us the 4T1 breast cancer cell line. We thank Qing Liu for technical guidance in flow cytometry. We also thank Charlesworth for polishing our manuscript.

Funding

This project was supported by National Key Research and Development Projects (2016YFC1303404 and 2016YFA0101103) of the Ministry of Science and Technology, project (81472824) of National Natural Science Foundation, and Guangdong Science and Technology Project (2015A020211009) from the Guangdong Science and Technology Innovation Commission, of the People's Republic of China.

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  1. Junxia Gao and ** Li

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  1. Junxia Gao
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  2. **anlin Yuan
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  3. Jia Yuan
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  4. Liang** Li
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JG and XY performed the experiments and wrote the manuscript. LL designed, proposed, and supervised this project and wrote the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Liang** Li.

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All authors declare no financial conflicts or competing interest.

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All animal studies were approved by **an University Experimental Animal Center and by the Ethics Committee of **an University (Approval number: IACUC-20190916-07).

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Gao, J., Yuan, X., Yuan, J. et al. Complete rejection of large established breast cancer by local immunochemotherapy with T cell activation against neoantigens. Cancer Immunol Immunother 70, 3291–3302 (2021). https://doi.org/10.1007/s00262-021-02919-2

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  • DOI: https://doi.org/10.1007/s00262-021-02919-2

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