The Journal of Experimental Medicine
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Published online 9 June 2003 doi:10.1084/jem.20021650
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© Rockefeller University Press, 0022-1007/2003/6/1667 $5.00
The Journal of Experimental Medicine, Volume 197, Number 12, 1667-1676

A Reversible Defect in Natural Killer T Cell Function Characterizes the Progression of Premalignant to Malignant Multiple Myeloma

Madhav V. Dhodapkar1,2, Matthew D. Geller1, David H. Chang1, Kanako Shimizu1, Shin-Ichiro Fujii1, Kavita M. Dhodapkar1 and Joseph Krasovsky1

1 Laboratory of Tumor Immunology and Immunotherapy, The Rockefeller University
2 Hematology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10021

Address correspondence to Madhav V. Dhodapkar, Laboratory of Tumor Immunology and Immunotherapy, The Rockefeller University, New York, NY 10021. Phone: 212-327-8114; Fax: 212-327-7119, E-mail: dhodapm{at}mail.rockefeller.edu

We studied the function of antitumor T and natural killer T (NKT) cells from the blood and tumor bed in 23 patients with premalignant gammopathy, nonprogressive myeloma, or progressive multiple myeloma. We show that antitumor killer T cells can be detected in patients with both progressive or nonprogressive myeloma. V{alpha}24+Vß11+ invariant NKT cells are detectable in the blood and tumor bed of all cohorts. However, freshly isolated NKT cells from both the blood and tumor bed of patients with progressive disease, but not nonprogressive myeloma or premalignant gammopathy, have a marked deficiency of ligand-dependent interferon-{gamma} production. This functional defect can be overcome in vitro using dendritic cells pulsed with the NKT ligand, {alpha}-galactosylceramide ({alpha}-GalCer). Fresh myeloma cells express CD1d, and can be efficiently killed by autologous NKT cells. We hypothesize that presentation of tumor derived glycolipids by myeloma cells leads to NKT dysfunction in vivo. These data demonstrate that clinical progression in patients with monoclonal gammopathies is associated with an acquired but potentially reversible defect in NKT cell function and support the possibility that these innate lymphocytes play a role in controlling the malignant growth of this incurable B cell tumor in patients.

Key Words: multiple myeloma • NKT cells • dendritic cells • interferon-{gamma} • immunotherapy


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