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Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma

2017; Impact Journals LLC; Volume: 8; Issue: 13 Linguagem: Inglês

10.18632/oncotarget.15368

1949-2553

Yago Pico de Coaña, Maria Wolodarski, Isabel Poschke, Yuya Yoshimoto, Yuan Yang, Maria Nyström, Ulrika Edbäck, Søren Brage, Andreas Lundqvist, Giuseppe Masucci, Johan Hansson, Rolf Kiessling,

Cancer Immunotherapy and Biomarkers

// Yago Pico de Coaña 1 , Maria Wolodarski 1, 2 , Isabel Poschke 3 , Yuya Yoshimoto 4 , Yuan Yang 1, 5 , Maria Nyström 1 , Ulrika Edbäck 1 , Suzanne Eghyazi Brage 1 , Andreas Lundqvist 1, 6 , Giuseppe V. Masucci 1, 2 , Johan Hansson 1, 2 , Rolf Kiessling 1 1 Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden 2 Karolinska University Hospital Solna, Stockholm, Sweden 3 Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany 4 Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan 5 Cancer Immunology and Immunotherapy Center, The Affiliated Hospital of Guiyang Medical College, Guiyang, People's Republic of China 6 Cell Therapies Institute, Nova Southeastern University, Fort Lauderdale, FL, USA Correspondence to: Yago Pico de Coaña, email: yagopico@gmail.com Keywords: melanoma, checkpoint blockade, CD8 effector memory T cells, ipilimumab, MDSC Received: August 08, 2016 Accepted: January 10, 2017 Published: February 16, 2017 ABSTRACT Ipilimumab has revolutionized malignant melanoma therapy, but a better understanding of the mechanisms behind treatment response and adverse effects is needed. In this work, the immune system of ipilimumab treated patients was monitored to investigate potential mechanisms of action that may correlate with treatment outcome. Blood samples from 43 advanced melanoma patients were taken before, during and at the end of treatment. Hematological parameters were measured and flow cytometry analysis was performed in fresh samples within two hours of sample collection. Strong differences in markers CD45RA, CCR7, HLA-DR and CD15 between fresh and cryopreserved samples were observed. Ipilimumab treatment increased absolute lymphocyte counts, eosinophils, effector T cells and their activation status, whilst diminishing the suppressive side of the immune response, acting on regulatory T cells and myeloid derived suppressor cells (MDSCs). These effects were visible after one ipilimumab infusion and, regarding eosinophil counts, correlated with onset of adverse events. Monocytic MDSCs were decreased in response to treatment only in patients with clinical benefit; additionally, patients with a lower frequency of these cells after the first ipilimumab infusion experienced increased overall survival. CD8 effector memory T cell frequencies at the end of treatment were higher in patients with clinical benefit and positively correlated with survival. These data show that a clinical response to ipilimumab not only requires reshaping T cell populations, but additionally involves a reduction in suppressive cells such as monocytic MDSCs. Our work could provide insight on predicting treatment outcome, assisting clinicians in offering the best personalized therapeutic approach.