Abstract
Monocytes are among the first cells to infiltrate the tumor microenvironment. The conversion of monocytes to suppressor cells in the tumor microenvironment is crucial in evasion of the immune response and tumor maintenance. Tumor cells may secrete products that promote the conversion of monocytes to suppressor cells. Cells secrete extracellular vesicles (EVs) containing cargos of genetic materials and proteins as a way to communicate with neighboring cells. During pathologic conditions like cancers, tumor cells increase their EVs production containing microRNA, RNA, and proteins that may affect the immune cell response, contributing to the immunosuppressive microenvironment. Our studies show that EVs secreted by a wide range of murine tumor cells, including osteosarcoma, glioma, colon carcinoma, sarcoma, and melanoma, can be taken up by bone marrow–derived monocytes. The monocytes that took up the EVs secreted by tumor cells matured toward an immune-suppressive phenotype by upregulating the expression of suppressive cytokines and effector molecules. The monocytes also downregulated MHC class II and costimulatory molecules while increasing the expression of PD-L1 on their surface after taking up EVs from tumor cells. Most importantly, monocytes exposed to EVs secreted by tumor cells suppressed activated Ag-specific CD4+ T cells. These results show that tumor cells from several different tumor types secrete EVs which promote the conversion of monocytes into suppressor cells, thus promoting immune evasion. These studies suggest that EVs secreted by tumors are potentially a new target for future cancer therapy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 647-658 |
| Number of pages | 12 |
| Journal | ImmunoHorizons |
| Volume | 5 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1 2021 |
Bibliographical note
Funding Information:Received for publication April 2, 2020. Accepted for publication July 14, 2021. Address correspondence and reprint requests to: Dr. Julie K. Olson, Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, 515 Delaware Street SE, Minneapolis, MN, 55455. E-mail address: jkolson@umn.edu ORCIDs: 0000-0002-6841-8361 (N.L.); 0000-0002-3210-618X (J.A.L.); 0000-0001-6398-7648 (J.F.M.). 1N.L. and J.A.L. contributed equally to this work. 2Current address: Department of Clinical Science and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA. This work was supported by the University of Minnesota College of Veterinary Medicine and the Animal Cancer Care and Research Program, and by a grant from the Morris Animal Foundation, D15CA-047. Analysis of EVs size was conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nano Coordinated Infrastructure Network under Award ECCS-1542202. Abbreviations used in this article: EV, extracellular vesicle; iNOS, inducible NO synthase; MDSC, myeloid-derived suppressor cell; miRNA, microRNA; SOCS3, suppressor of cytokines 3.
Publisher Copyright:
© 2021 The Authors
