The Antitumor Effect of Extracellular Vesicles Derived from Cytokine-activated CD8+ T Cells

Overview

Journal J Leukoc Biol

Publisher Oxford University Press

Specialty Allergy & Immunology

Date 2024 May 16

PMID 38753658

Authors

Lin Zhang

Yuan Meng

Yang An

Xuena Yang

Feng Wei

Xiubao Ren

Affiliations

Soon will be listed here.

Abstract

Extracellular vesicles (EVs) are nano-sized membrane particles secreted by various cell types that are involved in many important cellular processes. Recently, EVs originating from immune cells, such as dendritic cells, chimeric antigen receptor T cells, and natural killer cells, have attracted much attention because of their known direct and indirect antitumor activity. Here, we report the EVs released by cytokine-activated CD8+ T (caCD8) cells and its cytotoxicity against cancer cells. CaCD8 cells can release EVs following stimulation of CD8+ T cells with an anti-CD3 antibody and a cytokine cocktail ex vivo. The isolated vesicles have typical EV characteristics, such as an oval shape and a size distribution between 30 and 200 nm, as well as CD81 expression. Notably, caCD8-EVs displayed cytotoxicity against various cancer cells in vitro. Furthermore, mechanism analysis demonstrates that caCD8-EVs not only contain typical cytotoxic proteins (i.e. granzyme B and perforin), but also significantly enrich interferon γ (IFNγ) compared with caCD8 cells. EV-derived IFNγ participates in EV-induced apoptosis in cancer cells. Therefore, our data reveal antitumor effects of EVs secreted from caCD8 cells and the potential role of the EV-derived IFNγ.

References

Zhang L, Wang J, Wei F, Wang K, Sun Q, Yang F . Profiling the dynamic expression of checkpoint molecules on cytokine-induced killer cells from non-small-cell lung cancer patients. Oncotarget. 2016; 7(28):43604-43615. PMC: 5190047. DOI: 10.18632/oncotarget.9871. View

Franceschetti M, Pievani A, Borleri G, Vago L, Fleischhauer K, Golay J . Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. Exp Hematol. 2009; 37(5):616-628.e2. DOI: 10.1016/j.exphem.2009.01.010. View

Bigdeli A, Palchetti S, Pozzi D, Hormozi-Nezhad M, Bombelli F, Caracciolo G . Exploring Cellular Interactions of Liposomes Using Protein Corona Fingerprints and Physicochemical Properties. ACS Nano. 2016; 10(3):3723-37. DOI: 10.1021/acsnano.6b00261. View

Lugini L, Cecchetti S, Huber V, Luciani F, Macchia G, Spadaro F . Immune surveillance properties of human NK cell-derived exosomes. J Immunol. 2012; 189(6):2833-42. DOI: 10.4049/jimmunol.1101988. View

Fomina A, Deerinck T, Ellisman M, Cahalan M . Regulation of membrane trafficking and subcellular organization of endocytic compartments revealed with FM1-43 in resting and activated human T cells. Exp Cell Res. 2003; 291(1):150-66. PMC: 2749753. DOI: 10.1016/s0014-4827(03)00372-0. View

Liu L, Zhang W, Qi X, Li H, Yu J, Wei S . Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin Cancer Res. 2012; 18(6):1751-9. DOI: 10.1158/1078-0432.CCR-11-2442. View

Kursunel M, Esendagli G . The untold story of IFN-γ in cancer biology. Cytokine Growth Factor Rev. 2016; 31:73-81. DOI: 10.1016/j.cytogfr.2016.07.005. View

Linn Y, Lau S, Liu B, Ng L, Yong H, Hui K . Characterization of the recognition and functional heterogeneity exhibited by cytokine-induced killer cell subsets against acute myeloid leukaemia target cell. Immunology. 2008; 126(3):423-35. PMC: 2669823. DOI: 10.1111/j.1365-2567.2008.02910.x. View

Kowal J, Tkach M . Dendritic cell extracellular vesicles. Int Rev Cell Mol Biol. 2019; 349:213-249. DOI: 10.1016/bs.ircmb.2019.08.005. View

10.

Schmidt H, Gelhaus C, Nebendahl M, Lettau M, Lucius R, Leippe M . Effector granules in human T lymphocytes: proteomic evidence for two distinct species of cytotoxic effector vesicles. J Proteome Res. 2011; 10(4):1603-20. DOI: 10.1021/pr100967v. View

11.

Moller A, Lobb R . The evolving translational potential of small extracellular vesicles in cancer. Nat Rev Cancer. 2020; 20(12):697-709. DOI: 10.1038/s41568-020-00299-w. View

12.

Balint S, Muller S, Fischer R, Kessler B, Harkiolaki M, Valitutti S . Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells. Science. 2020; 368(6493):897-901. PMC: 7116847. DOI: 10.1126/science.aay9207. View

13.

Barthson J, Germano C, Moore F, Maida A, Drucker D, Marchetti P . Cytokines tumor necrosis factor-α and interferon-γ induce pancreatic β-cell apoptosis through STAT1-mediated Bim protein activation. J Biol Chem. 2011; 286(45):39632-43. PMC: 3234786. DOI: 10.1074/jbc.M111.253591. View

14.

Peters P, Borst J, Oorschot V, Fukuda M, Krahenbuhl O, Tschopp J . Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med. 1991; 173(5):1099-109. PMC: 2118839. DOI: 10.1084/jem.173.5.1099. View

15.

Meldolesi J . Exosomes and Ectosomes in Intercellular Communication. Curr Biol. 2018; 28(8):R435-R444. DOI: 10.1016/j.cub.2018.01.059. View

16.

Mulcahy L, Pink R, Carter D . Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014; 3. PMC: 4122821. DOI: 10.3402/jev.v3.24641. View

17.

Mata-Molanes J, Sureda Gonzalez M, Valenzuela Jimenez B, Martinez Navarro E, Brugarolas Masllorens A . Cancer Immunotherapy with Cytokine-Induced Killer Cells. Target Oncol. 2017; 12(3):289-299. DOI: 10.1007/s11523-017-0489-2. View

18.

Thiery J, Keefe D, Saffarian S, Martinvalet D, Walch M, Boucrot E . Perforin activates clathrin- and dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzyme-mediated apoptosis. Blood. 2009; 115(8):1582-93. PMC: 2830763. DOI: 10.1182/blood-2009-10-246116. View

19.

Ruiz-Ruiz C, Ruiz de Almodovar C, Rodriguez A, Ortiz-Ferron G, Redondo J, Lopez-Rivas A . The up-regulation of human caspase-8 by interferon-gamma in breast tumor cells requires the induction and action of the transcription factor interferon regulatory factor-1. J Biol Chem. 2004; 279(19):19712-20. DOI: 10.1074/jbc.M313023200. View

20.

Pievani A, Borleri G, Pende D, Moretta L, Rambaldi A, Golay J . Dual-functional capability of CD3+CD56+ CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity. Blood. 2011; 118(12):3301-10. DOI: 10.1182/blood-2011-02-336321. View