Research Papers:

PD1 blockade enhances cytotoxicity of in vitro expanded natural killer cells towards myeloma cells

Yanan Guo, Xiaoli Feng, Yang Jiang, Xiaoyun Shi, Xiangling Xing, Xiaoli Liu, Nailin Li, Bengt Fadeel and Chengyun Zheng _

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Oncotarget. 2016; 7:48360-48374. https://doi.org/10.18632/oncotarget.10235

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Yanan Guo1,2,3, Xiaoli Feng2,4, Yang Jiang1,2,3, Xiaoyun Shi1,2,3, Xiangling Xing1,2,3, Xiaoli Liu1,2,3, Nailin Li3,5, Bengt Fadeel6,7, Chengyun Zheng1,2,3,7

1Hematology Department, The Second Hospital of Shandong University, Jinan, China

2Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China

3Shandong University-Karolinska Institutet Collaborative Laboratory for Stem Cell Research, The Second Hospital of Shandong University, Jinan, China

4Clinical Laboratory Department of The Second Hospital, Shandong University, Jinan, China

5Department of Medicine-Solna, Clinical Pharmacology Group, Karolinska Institutet, Karolinska University Hospital-Solna, Stockholm, Sweden

6Karolinska Institutet, Institute of Environmental Medicine, Division of Molecular Toxicology, Stockholm, Sweden

7Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

Correspondence to:

Chengyun Zheng, email: [email protected]

Keywords: natural killer cells, in vitro expansion, PD1, anti-tumor activity, myeloma

Received: April 05, 2016     Accepted: June 03, 2016     Published: June 23, 2016


Aiming for an adoptive natural killer (NK) cell therapy, we have developed a novel protocol to expand NK cells from peripheral blood. With this protocol using anti-human CD16 antibody and interleukin (IL)-2, NK (CD3-CD56+) cells could be expanded about 4000-fold with over 70% purity during a 21-day culture. The expanded NK (exNK) cells were shown to be highly cytotoxic to multiple myeloma (MM) cells (RPMI8226) at low NK-target cell ratios. Furthermore, NK cells expanded in the presence of a blocking antibody (exNK+PD1-blockage) against programmed cell death protein-1 (PD1), a key counteracting molecule for NK and T cell activity, demonstrated more potent cytolytic activity against the RPMI8226 than the exNK cells without PD1 blocking. In parallel, the exNK cells showed significantly higher expression of NK activation receptors NKG2D, NKp44 and NKp30. In a murine model of MM, transfusion of exNK cells, exNK+PD1-blockage, and exNK plus intratumor injection of anti-PD-L2 antibody (exNK+PD-L2 blockage) all significantly suppressed tumor growth and prolonged survival of the myeloma mice. Importantly, exNK+PD1-blockage presented more efficient therapeutic effects. Our results suggest that the NK cell expansion protocol with PD1 blockade presented in this study has considerable potential for the clinical application of allo- and auto-NK cell-based therapies against malignancies.

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