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Intravenous injection of tumor extracellular vesicles suppresses tumor growth by reducing the regulatory T cell phenotype

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

Colorectal cancer is a disease of unmet medical need. Although extracellular vesicles (EVs) have been implicated in anti-tumor responses, discrepancies were observed among studies. We analyzed the role of tumor-derived EVs (TEVs) in tumor progression in vivo by focusing on regulatory T (Treg) cells, which play essential roles in tumor development and progression.

Methods

A mouse model of colorectal cancer lung metastasis was generated using BALB/c mice by tail vein injection of the BALB/c colon adenocarcinoma cell line Colon-26. TEVs derived from Colon-26 and BALB/c lung squamous cell carcinoma ASB-XIV were retrieved from the culture media supernatants. A TEV equivalent to 10 µg protein was injected every other day for 2 weeks.

Results

Histology and immunohistochemistry studies revealed that lung tumors reduced in the Colon-26-EV group when compared to the phosphate-buffered saline (PBS) group. The population of CD4 + FoxP3 + cells in the lung was upregulated in the PBS group mice when compared to the healthy mice (P < 0.001), but was significantly downregulated in the Colon-26-EV group mice when compared to the PBS group mice (P < 0.01). Programmed cell death protein 1, glucocorticoid-induced TNFR-related protein, and CD69 expression in lung Treg cells were markedly upregulated in the PBS group when compared to the healthy mice, but downregulated in the Colon-26-EV group when compared to the PBS group. The changes in expression were dose-dependent for Colon-26-EVs. ASB-EVs also led to significantly downregulated Treg cell expression, although non-cancer line 3T3-derived EVs did not.

Conclusion

Our study suggests that TEVs possess components for tumor suppression.

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Data availability

The datasets of this study are available from the corresponding author upon reasonable request.

Abbreviations

CFSE:

Carboxyfluorescein succinimidyl ester

CRC:

Colorectal cancer

DC:

Dendritic cells

EV:

Extracellular vesicle

FBS:

Fetal bovine serum

H&E:

Hematoxylin and eosin

ICI:

Immune checkpoint inhibitor

NTA:

Nanoparticle tracking analysis

PBS:

Phosphate-buffered saline

Treg:

Regulatory T

TEM:

Transmission electron microscopy

TME:

Tumor microenvironment

TEVs:

Tumor-derived EVs

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Acknowledgements

We would like to thank Editage (www.editage.jp) for English language editing.

Funding

This study was funded by (1) Grant-in-Aid for Young Scientists JSPS KAKENHI Grant Number JP20K17066, (2) Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, (3) Grant-in-Aid for Scientific Research (C) of the Ministry of Culture and Science of Japan (20590810, 23591017, 24591020, 12008507, 17877850, 17K09468, 15K09052), (4) the Research Program on Intractable Diseases, from the Ministry of Labor and Welfare of Japan, and (5) grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, (6) the Research Program from the Japan Medical Research and Development (AMED) (17824893).

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Authors and Affiliations

  1. Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan

    Sanshiro Kobayashi, Takashi Tomiyama, Naohiro Nakamura, Masataka Masuda, Yasushi Matsumoto, Yusuke Honzawa, Tomomitsu Tahara, Tsukasa Ikeura, Toshiro Fukui, Kazuichi Okazaki & Makoto Naganuma

  2. Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan

    Naoyuki Kondo

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SK and TT designed the study and wrote the initial draft of the manuscript. SK, TT, NK, NN, MM, and YM performed the experiments. YH, TT, TI, TF, KO, and MN contributed to the analysis and interpretation of data and assisted in the preparation of the manuscript. All other authors have contributed to data collection and interpretation and critically reviewed the manuscript.

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Correspondence to Takashi Tomiyama.

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This research has been approved by Animal Ethics Committee (#18-115(01)) and Recombinant DNA Experiments Committee (#30-012-1) of Kansai Medical University.

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Kobayashi, S., Kondo, N., Tomiyama, T. et al. Intravenous injection of tumor extracellular vesicles suppresses tumor growth by reducing the regulatory T cell phenotype. Cancer Immunol Immunother 72, 3651–3664 (2023). https://doi.org/10.1007/s00262-023-03517-0

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