Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo.
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. (Blood. 2001;97:3132-3137)
Koh
C Y
CY
Laboratory of Leukocyte Biology, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD, USA.
Blazar
B R
BR
George
T
T
Welniak
L A
LA
Capitini
C M
CM
Raziuddin
A
A
Murphy
W J
WJ
Bennett
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D000950:Antigens, Ly / Q000276:immunology; D002455:Cell Division; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism / Q000494:pharmacology; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D007942:Leukemia, Experimental / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D055650:NK Cell Lectin-Like Receptor Subfamily A; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D055630:Receptors, NK Cell Lectin-Like; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D015395:Histocompatibility Antigens Class I; D007140:Immunoglobulin Fab Fragments; C527091:Klra3 protein, mouse; D037181:Lectins, C-Type; C408248:Ly49I antigen; D008562:Membrane Glycoproteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like