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Letters to the Editor
CCL2 and CCL5) secreted by NK cells in the same co-cul- ture conditions (Online Supplementary Figure S3E).
A recent study also demonstrated that continual lenalidomide treatment of MM patients did not improve NK-cell function with a lower ADCC response and decreased reactivity against K562 target cells.13 These observations are similar to our findings suggesting that lenalidomide treatment alone is insufficient to rescue MM patient NK cell function in vivo. In contrast, in vitro lenalidomide-treated HD NK cells up-regulate genes for IL2/STAT5, mTORC1 and TNF signalling pathway sug- gesting activation (data not shown).
In summary, our results showed that NK cells in MM patients are chronically stimulated with an increase in terminally differentiated NK cells and loss of regulation of activation. This scenario is plausible considering the bone marrow is a site of myeloma disease as well as NK-cell development and maturation. Thus repetitive stimulation by the myeloma cells would impact NK-cell maturation. In addition, we showed lenalidomide and dexamethasone combination treatment did not repair this intrinsic NK-cell defect in MM. In order to address this issue, future combination immunotherapy approach- es could use a tumor targeting antibody (e.g., Daratumumab, anti-CD38) with agonistic anti-CD137 mAb14 or anti-TIGIT15 to rescue NK-cell dysfunction in MM.
Criselle D’Souza,1,2* Simon P. Keam,1,2,3 Han Xian Aw Yeang,1
Michael Neeson,1 Kelden Richardson,1 Andy K. Hsu,1
1 4° 5° Rachael Canfield, Natalie Bezman, Michael Robbins,
Hang Quach,6,7 David S. Ritchie,3,7,8 Simon J. Harrison,3,8 Joseph A. Trapani,1,2 H. Miles Prince,1,2,8 Paul A. Beavis,1,2 Phillip K. Darcy1,2 and Paul J. Neeson1,2*
1Cancer Immunology Program, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; 2Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia;
3Tumor Suppression and Cancer Sex Disparity Laboratory, Sir Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; 4Oncology Discovery Research, Bristol-Myers Squibb, Redwood City, CA, USA; 5Translational Medicine, Bristol-Myers Squibb, Cambridge, MA, USA; 6Department of Hematology, St Vincent’s Hospital, Melbourne, Victoria, Australia; 7Faculty of Medicine, University of Melbourne, Melbourne, Victoria, Australia and 8Clinical Hematology, Sir Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne, Victoria, Australia
°NB current address: Arsenal Bio, San Francisco, CA, USA
°MR current address: io904 LLC, Jacksonville Beach, FL, USA
Correspondence: PAUL J. NEESON - paul.neeson@petermac.org
CRISELLE D’SOUZA - criselle.dsouza@petermac.org
doi:10.3324/haematol.2020.277525
Received: December 3, 2020.
Accepted: April 29, 2021.
Pre-published: May 20, 2021.
Disclosures: PJN received research funding from BMS for this project.
Contributions: CD, AKH, HXAY, MN, RC performed experi-
ments; CD, AKH, SPK, MN, RC, KR analyzed experiment data; CD and PJN interpreted, analyzed and wrote the manuscript;
PJN conceived and supervised the project; HQ, DSR, SJH,
and HMP conducted the clinical trials; NB, MR, JAT, HMP, PAB, PKD helped interpret data. All authors reviewed, edited and approved the manuscript.
Acknowledgments: we thank Dr Jessica Li, Dr Deborah Meyran and Dr Minyu Wang for critical review of the manuscript.
Funding: funding for this study was provided by Cure Cancer Australia, Australian NHMRC program grant No. 113 2373 and Bristol-Myers Squibb.
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