Melanoma-released exosomes directly activate the mitochondrial apoptotic pathway of CD4+ T cells through their microRNA cargo

Ji Zhou; Yi Yang; WenWen Wang; Yuan Zhang; ZhengRong Chen; ChuangLi Hao; JinPing Zhang

doi:10.1016/j.yexcr.2018.08.030

Melanoma-released exosomes directly activate the mitochondrial apoptotic pathway of CD4⁺ T cells through their microRNA cargo

Exp Cell Res. 2018 Oct 15;371(2):364-371. doi: 10.1016/j.yexcr.2018.08.030. Epub 2018 Aug 25.

Authors

Ji Zhou¹, Yi Yang¹, WenWen Wang¹, Yuan Zhang², ZhengRong Chen³, ChuangLi Hao³, JinPing Zhang⁴

Affiliations

¹ Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, People's Republic of China.
² Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, People's Republic of China.
³ Department of respiratory disease, Children's hospital of Soochow University, Suzhou, Jiangsu Province 215025, People's Republic of China.
⁴ Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, People's Republic of China. Electronic address: [email protected].

PMID: 30149000
DOI: 10.1016/j.yexcr.2018.08.030

Abstract

Tumor-derived exosomes (TEX) play an important role in the escape of tumor cells from immune surveillance. However, the details of the mechanism are not fully understood. In this study, the apoptosis of CD4⁺ T cells increased during treatment with B16-derived exosomes in vitro and in vivo, resulting in accelerated growth of melanoma cells in mice. While the release of exosomes was blocked by disrupting the expression of Rab27a, tumor growth was clearly inhibited, and the percentage of T cells in the tumor environment increased. At the same time, Western blot showed that TEX could increase the activation of caspase-3, caspase-7 and caspase-9 but not caspase-8, down-regulating the anti-apoptotic proteins, including BCL-2, MCL-1 and BCL-xL in CD4⁺ T cells, and indicating that the TEX activates the mitochondrial apoptotic pathway of CD4⁺ T cells. These reductions were probably associated with the release of microRNAs, such as miR-690, from TEX to T cells. Our present study reveals for the first time that melanoma-released exosomes may directly activate the mitochondrial apoptotic pathway of CD4⁺ T cells through their microRNA cargo.

Keywords: Apoptosis; Exosomes; T cells; Tumor microenvironment; microRNAs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics*
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / metabolism*
Carcinoma, Lewis Lung / genetics
Carcinoma, Lewis Lung / metabolism
Carcinoma, Lewis Lung / pathology
Caspase 3 / genetics
Caspase 3 / metabolism
Caspase 7 / genetics
Caspase 7 / metabolism
Caspase 9 / genetics
Caspase 9 / metabolism
Cell Line, Tumor
Cell Proliferation
Exosomes / chemistry
Exosomes / metabolism*
Exosomes / pathology
Female
Gene Expression Regulation
Mammary Neoplasms, Animal / genetics
Mammary Neoplasms, Animal / metabolism
Mammary Neoplasms, Animal / pathology
Melanoma, Experimental / chemistry*
Melanoma, Experimental / genetics
Melanoma, Experimental / metabolism
Melanoma, Experimental / pathology
Mice
Mice, Inbred C57BL
MicroRNAs / genetics*
MicroRNAs / metabolism
Mitochondria / metabolism*
Mitochondria / pathology
Myeloid Cell Leukemia Sequence 1 Protein / genetics
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Primary Cell Culture
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Signal Transduction
bcl-X Protein / genetics
bcl-X Protein / metabolism

Substances

Bcl2l1 protein, mouse
Mcl1 protein, mouse
MicroRNAs
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2
bcl-X Protein
Bcl2 protein, mouse
Casp3 protein, mouse
Casp7 protein, mouse
Casp9 protein, mouse
Caspase 3
Caspase 7
Caspase 9