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Isolated limb perfusion with melphalan activates interferon-stimulated genes to induce tumor regression in patients with melanoma in-transit metastasis

Journal article
Authors Junko Johansson
Roberta Kiffin
Ebru Aydin
Malin S. Nilsson
Kristoffer Hellstrand
Per Lindnér
Peter Naredi
Roger Olofsson Bagge
Anna Martner
Published in Oncoimmunology
Volume 9
Issue 1
ISSN 2162-402X
Publication year 2020
Published at Institute of Clinical Sciences, Department of Surgery
Sahlgrenska Cancer Center
Wallenberg Centre for Molecular and Translational Medicine
Institute of Biomedicine, Department of Infectious Medicine
Language en
Links dx.doi.org/10.1080/2162402x.2019.16...
Keywords ISG; Melanoma; T cell chemotaxis; chemokines; isolated limb perfusion; melphalan
Subject categories Cancer and Oncology

Abstract

Hyperthermic isolated limb perfusion (ILP) with high-dose melphalan is a treatment option for melanoma patients with metastasis confined to limbs (in-transit metastasis). The therapy entails a complete response (CR) rate of 50-70%. Cellular immunity is proposed to impact on the clinical efficacy of ILP, but the detailed aspects of ILP-induced immune activation remain to be explored. For this study, we explored the potential role of interferon-stimulated gene (ISG) products, including CXCL10, CCL2, PD-L2 and IFN-gamma along with expression of their cognate receptors CXCR3, CCR4, CCR5 and PD-1 on lymphocytes, for the clinical efficacy of ILP. Patients with high serum levels of CXCL10, CCL2, PD-L2 and IFN-gamma were more likely to achieve CR after ILP. Additionally, the expression of CXCR3, CCR4 and CCR5 on T cells and/or natural killer (NK) cells was enhanced by ILP. Peripheral blood mononuclear cells (PBMCs) secreted high levels of CXCL10, CCL2 and IFN-gamma in response to co-culture with melphalan-exposed melanoma cells in vitro. Activated T cells migrated toward supernatants from these co-cultures. Furthermore, melphalan-exposed melanoma cells triggered upregulation of CXCR3, CCR4, CCR5 and PD-1 on co-cultured T cells and/or NK cells. Our results suggest that constituents released from melphalan-exposed melanoma cells stimulate the ISG axis with ensuing formation of chemokines and upregulation of chemokine receptor expression on anti-neoplastic immune cells, which may contribute in ILP-induced tumor regression.

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