In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: maintained tolerance to normal cells even in the presence of IL-2.
Missing-self-reactivity can be mimicked by blocking self-specific inhibitory receptors on NK cells, leading to increased rejection of syngeneic tumor cells. Using a mouse model, we investigated whether Ab-mediated blocking of inhibitory receptors, to a degree where NK cells rejected syngeneic tumor cells, would still allow self-tolerance toward normal syngeneic cells. Ly49C/I inhibitory receptors on C57BL/6 (H-2(b)) NK cells were blocked with F(ab')(2) fragments of the mAb 5E6. Inhibitory receptor blockade in vivo caused rejection of i.v. inoculated fluorescence-labeled syngeneic lymphoma line cells but not of syngeneic spleen cells, BM cells or lymphoblasts. The selective rejection of tumor cells was NK cell-dependent and specifically induced by Ly49C/I blockade. Moreover, selective tumor rejection was maintained after treatment with 5E6 F(ab')(2) for 9 wk, arguing against the induction of NK cell anergy or autoreactivity during this time. Combination therapy using 5E6 F(ab')(2) together with high dose IL-2 treatment further increased lymphoma cell rejection. In addition, combination therapy reduced growth of melanoma cell line tumors established by s.c. inoculation 3 days before start of treatment. Our results demonstrate that inhibitory receptor blockade does not result in attack on normal cells, despite potent reactivity against MHC class I-expressing tumors.
Vahlne
Gustaf
G
Department for Microbiology, Tumor and Cell Biology and Strategic Research Center for Studies of Integrative Recognition in the Immune System (IRIS), Karolinska Institutet, Stockholm, Sweden.
Lindholm
Katja
K
Meier
Anders
A
Wickström
Stina
S
Lakshmikanth
Tadepally
T
Brennan
Frank
F
Wilken
Michael
M
Nielsen
Rikke
R
Romagné
François
F
Wagtmann
Nicolai R
NR
Kärre
Klas
K
Johansson
Maria H
MH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D002469:Cell Separation; D005434:Flow Cytometry; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000276:immunology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008223:Lymphoma / Q000628:therapy; D051379:Mice; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000037:antagonists & inhibitors* / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D017634:Self Tolerance / Q000187:drug effects / Q000276:immunology*
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007376:Interleukin-2; C527092:Klra4 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A