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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3132-3137
IMMUNOBIOLOGY
Augmentation of antitumor effects by NK cell inhibitory
receptor blockade in vitro and in vivo
Crystal Y. Koh,
Bruce R. Blazar,
Thaddeus George,
Lisbeth A. Welniak,
Christian
M. Capitini,
Arati Raziuddin,
William J. Murphy, and
Michael Bennett
From the Laboratory of Leukocyte Biology, National
Cancer Institute-Frederick Cancer Research and Development
Center; and the Intramural Research Support Program,
SAIC-Frederick, Frederick, MD; the Department of Pediatrics,
Division of Bone Marrow Transplantation, University of Minnesota Cancer
Center, Minneapolis, MN; and the Department of Pathology, University of
Texas Southwestern Medical Center, Dallas, TX.
Subsets of natural killer (NK) cells are characterized by the
expression of inhibitory and/or stimulatory receptors specific for
major histocompatibility complex (MHC) class I determinants. In mice,
these include the Ly49 family of molecules. One mechanism by which
tumor cells may evade NK cell killing is by expressing the appropriate
MHC class I and binding inhibitory Ly49 receptors. Therefore, the
question of whether blocking the interaction between the Ly49
inhibitory receptors on NK and MHC class I cells on tumor cells
augments antitumor activity was investigated. Blockade of Ly49C
and I inhibitory receptors using F(ab')2 fragments of the 5E6 monoclonal antibody (mAb) resulted in increased cytotoxicity against syngeneic tumors and decreased tumor cell growth in vitro. The
effect of 5E6 F(ab')2 was specific for the MHC of the
tumor, as the use of F(ab')2 of the mAb against Ly49G2
failed to increase NK activity. Treatment of leukemia-bearing mice with
5E6 F(ab')2 fragments or adoptive transfer of NK cells
treated ex vivo with the F(ab')2 resulted in significant
increases in survival. These results demonstrate that blockade of NK
inhibitory receptors enhances antitumor activity both in vitro and in
vivo, suggesting that NK inhibitory receptors can be responsible for
diminishing antitumor responses. Therefore, strategies to block
inhibitory receptors may be of potential use in increasing the efficacy
of immunotherapy.
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