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Isolated Limb Perfusion With Melphalan Triggers Immune Activation in Melanoma Patients

Artikel i vetenskaplig tidskrift
Författare Junko Johansson
Roberta Kiffin
Annica Andersson
Per Lindnér
Peter Naredi
Roger Olofsson Bagge
Anna Martner
Publicerad i Frontiers in Oncology
Volym 8
ISSN 2234-943X
Publiceringsår 2018
Publicerad vid Institutionen för kliniska vetenskaper, Avdelningen för kirurgi
Sahlgrenska Cancer Center
Institutionen för biomedicin, avdelningen för infektionssjukdomar
Språk en
Länkar dx.doi.org/10.3389/fonc.2018.00570
Ämnesord melanoma, isolated limb perfusion, melphalan, monocytes, cytotoxic T cells, in-transit melanoma, t-cells, calreticulin, chemotherapy, lymphocytes, metastases, monocytes, antigens
Ämneskategorier Cancer och onkologi

Sammanfattning

Hyperthermic isolated limb perfusion with melphalan (M-ILP) is a treatment option for melanoma patients with metastases confined to the limbs. This study aimed at defining the role of cellular immunity for the clinical response to M-ILP in melanoma patients. It was observed that patients with enhanced cytotoxic CD8(+) T cell reactivity to common antigens (HCMV/EBV/influenza virus) prior to M-ILP were more likely to achieve a complete disappearance of macroscopic tumors (complete response). Following M-ILP treatment, the proportions of CD16(+) intermediate and non-classical monocytes in peripheral blood were significantly enhanced along with induction of HLA-DR on CD4(+) and CD8(+) T cells. For further studies of the mechanism behind melphalan-induced immune activation an in vitro model, aiming at mimicking the clinical M-ILP protocol, was established, where PBMCs were co-cultured with melanoma cells, which had been pre-exposed to melphalan under mild hyperthermia. Upon exposure to melphalan, melanoma cells showed increased expression of immune-related markers including MHC class I and Hsp70. Moreover, when the melphalan-treated melanoma cells were co-cultured with PBMCs, this triggered an increased proportion of CD33(+)CD14(+)CD16(++) non-classical monocytes among the PBMCs. Furthermore, the melphalan-treated melanoma cells stimulated the expansion of CD8(+) T cells in the co-cultured PBMCs. These cells produced enhanced levels of IFN-gamma and granzyme B and were capable of killing melanoma cells. To further verify an immunogenic role of melphalan, mice were vaccinated with melphalan-exposed murine melanoma cells. When challenged with live melanoma cells, vaccinated mice showed reduced tumor growth and enhanced infiltration of tumor-specific T cells into tumors. We conclude that melphalan-exposed melanoma cells trigger expansion of CD16(+) monocytes and activate cytotoxic T cells and that these events may contribute to the antitumoral efficacy of M-ILP.

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