Oncotarget

Research Papers:

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

Yago Pico de Coana _, Maria Wolodarski, Isabel Poschke, Yuya Yoshimoto, Yuan Yang, Maria Nystrom, Ulrika Edback, Suzanne Eghyazi Brage, Andreas Lundqvist, Giuseppe V. Masucci, Johan Hansson and Rolf Kiessling

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Oncotarget. 2017; 8:21539-21553. https://doi.org/10.18632/oncotarget.15368

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Abstract

Yago Pico de Coaña1, Maria Wolodarski1,2, Isabel Poschke3, Yuya Yoshimoto4, Yuan Yang1,5, Maria Nyström1, Ulrika Edbäck1, Suzanne Eghyazi Brage1, Andreas Lundqvist1,6, Giuseppe V. Masucci1,2, Johan Hansson1,2, Rolf Kiessling1

1Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden

2Karolinska University Hospital Solna, Stockholm, Sweden

3Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany

4Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

5Cancer Immunology and Immunotherapy Center, The Affiliated Hospital of Guiyang Medical College, Guiyang, People’s Republic of China

6Cell Therapies Institute, Nova Southeastern University, Fort Lauderdale, FL, USA

Correspondence to:

Yago Pico de Coaña, email: [email protected]

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.


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