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, Michael Bennett

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122 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3132-3137
Number of pages6
JournalBlood
Volume97
Issue number10
DOIs
Publication statusPublished - May 15 2001

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ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Koh, C. Y., Blazar, B. R., George, T., Welniak, L. A., Capitini, C. M., Raziuddin, A., ... Bennett, M. (2001). Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo. Blood, 97(10), 3132-3137. https://doi.org/10.1182/blood.V97.10.3132