Cytokine-Induced Killer Cells Kill Chemo-surviving Melanoma Cancer Stem Cells
Autor: | Dario Sangiolo, Anna Sapino, Ymera Pignochino, Martina Sanlorenzo, Valentina Martin, Ramona Rotolo, Giulia Mesiano, Giulia Cattaneo, Loretta Gammaitoni, Rebecca Senetta, Alessandro Zaccagna, Valeria Leuci, Valentina Coha, Marco Macagno, Alberto Pisacane, Michela Cangemi, Lidia Giraudo, Giovanni Grignani, Francesco Sassi, Massimo Aglietta, Susanna Gallo, Fabrizio Carnevale-Schianca |
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Rok vydání: | 2017 |
Předmět: |
Cytotoxicity
Immunologic Proto-Oncogene Proteins B-raf 0301 basic medicine Cancer Research Carcinogenesis medicine.medical_treatment Biology Immunotherapy Adoptive Nitrosourea Compounds Mice 03 medical and health sciences Cytokine-Induced Killer Cells Organophosphorus Compounds 0302 clinical medicine In vivo Cancer stem cell Cell Line Tumor Oximes medicine Animals Humans CIK Melanoma Cytokine-induced killer cell Cancer stem cells Lentivirus Imidazoles immunotherapy Dabrafenib Immunotherapy medicine.disease Xenograft Model Antitumor Assays 030104 developmental biology Oncology Drug Resistance Neoplasm Cell culture 030220 oncology & carcinogenesis Immunology Neoplastic Stem Cells Cancer research Neoplasm Recurrence Local Stem cell medicine.drug |
Zdroj: | Clinical Cancer Research. 23:2277-2288 |
ISSN: | 1557-3265 1078-0432 |
Popis: | Purpose: The MHC-unrestricted activity of cytokine-induced killer (CIK) cells against chemo-surviving melanoma cancer stem cells (mCSC) was explored, as CSCs are considered responsible for chemoresistance and relapses. Experimental Design: Putative mCSCs were visualized by engineering patient-derived melanoma cells (MC) with a lentiviral vector encoding eGFP under expression control by stemness gene promoter oct4. Their stemness potential was confirmed in vivo by limiting dilution assays. We explored the sensitivity of eGFP+ mCSCs to chemotherapy (CHT), BRAF inhibitor (BRAFi) or CIK cells, as single agents or in sequence, in vitro. First, we treated MCs in vitro with fotemustine or dabrafenib (BRAF-mutated cases); then, surviving MCs, enriched in mCSCs, were challenged with autologous CIK cells. CIK cell activity against chemoresistant mCSCs was confirmed in vivo in two distinct immunodeficient murine models. Results: We visualized eGFP+ mCSCs (14% ± 2.1%) in 11 MCs. The tumorigenic precursor rate in vivo was higher within eGFP+ MCs (1/42) compared with the eGFP− counterpart (1/4,870). In vitro mCSCs were relatively resistant to CHT and BRAFi, but killed by CIK cells (n = 11, 8/11 autologous), with specific lysis ranging from 95% [effector:tumor ratio (E:T), 40:1] to 20% (E:T 1:3). In vivo infusion of autologous CIK cells into mice bearing xenografts from three distinct melanomas demonstrated significant tumor responses involving CHT-spared eGFP+ mCSCs (P = 0.001). Sequential CHT–immunotherapy treatment retained antitumor activity (n = 12, P = 0.001) reducing mCSC rates (P = 0.01). Conclusions: These findings are the first demonstration that immunotherapy with CIK cells is active against autologous mCSCs surviving CHT or BRAFi. An experimental platform for mCSC study and rationale for CIK cells in melanoma clinical study is provided. Clin Cancer Res; 23(9); 2277–88. ©2016 AACR. |
Databáze: | OpenAIRE |
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