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Analytic and Dynamic Secretory Profile of Patient-Derived Cytokine-Induced Killer Cells

Authors
Giulia Mesiano, Roberta Zini, Giulia Montagner, Nicoletta Bianchi, Rossella Manfredini, Antonella Chillemi, Massimo Aglietta, Giovanni Grignani, Ilaria Lampronti, Erika Fiorino, Fabio Malavasi, Dario Sangiolo, Roberto Gambari, and Davide Ferrari
Abstract
Adoptive immunotherapy with cytokine induced killer (CIK) cells has shown antitumor activity against several kinds of cancer in preclinical models and clinical trials. CIK cells are a subset of ex vivo expanded T lymphocytes with T-NK phenotype and MHC-unrestricted antitumor activity. The literature provides scant information on cytokines, chemokines and growth factors secreted by CIK cells. Therefore, we investigated the secretory profile of CIK cells generated from tumor patients. The secretome analysis was performed at specific time points (d 1, d 14 and d 21) of CIK cell expansion. Mature CIK cells (d 21) produce a great variety of interleukins and secreted proteins that can be divided into three groups based on their secretion quantity: high (interleukin [IL]-13, regulated on activation normal T cell expressed and secreted [RANTES] chemokine, MIP-1α and 1β), medium (IL-1Ra, IL-5, IL-8, IL-10, IL-17, IP-10, INF-γ, vascular endothelial growth factor [VEGF] and granulocyte-macrophage colony-stimulating factor [GM-CSF]) and low (IL-1β, IL-4, IL-6, IL-7, IL-9, IL-12, IL-15, eotaxin, platelet-derived growth factor-bb, basic fibroblast growth factor, G-CSF and monocyte chemoattractant protein [MCP]-1). Moreover, comparing peripheral blood mononuclear cells (PBMCs) (d 1) and mature CIK cells (d 14 and 21) secretomes, we observed that IL-5, IL-10, IL-13, GM-CSF and VEGF were greatly upregulated, while IL-1β, IL-6, IL-8, IL-15, IL-17, eotaxin, MCP-1 and RANTES were downregulated. We also performed a gene expression profile analysis of patient-derived CIK cells, showing that mRNA for the different cytokines and secreted proteins was modulated during PBMC-to-CIK differentiation. We highlight previously unknown secretory properties and provide, for the first time, a comprehensive molecular characterization of CIK cells. Our findings provide a rationale to explore the functional implications and possible therapeutic modulation of CIK secretome.
Volume
2017
Page Range
235-246
DOI
10.2119/molmed.2017.00084
Date Published
August 9, 2017
Article PDF
17_084_Mesiano.pdf6037 KB
Supplemental Data
17_084_Mesiano_Suppl.pdf5636 KB
Keywords
Mesiano, Zini, Montagner, Bianchi, Manfredini, Chillemi, Aglietta, Grignani, Lampronti, Fiorino, Malavasi, Sangiolo, Gambari, Ferrari, adoptive immunotherapy, cytokine-induced killer (CIK) cells, antitumor activity, metastatic solid tumors, secretome
Article Type
Research Article