1. In vivotumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL-2
- Author
-
Stina L. Wickström, Anders Meier, Tadepally Lakshmikanth, Michael Wilken, Frank Brennan, Maria H. Johansson, Nicolai Wagtmann, Klas Kärre, Katja Lindholm, François Romagné, Gustaf Vahlne, and Rikke Christina Nielsen
- Subjects
Lymphoma ,medicine.medical_treatment ,Immunology ,Cell Separation ,Immunoglobulin Fab Fragments ,Mice ,Interleukin 21 ,MHC class I ,medicine ,Animals ,Immunology and Allergy ,Lymphokine-activated killer cell ,biology ,Janus kinase 3 ,Lymphoblast ,Antibodies, Monoclonal ,Neoplasms, Experimental ,Immunotherapy ,Flow Cytometry ,Killer Cells, Natural ,Self Tolerance ,Cytokine ,biology.protein ,Interleukin 12 ,Cancer research ,Interleukin-2 ,NK Cell Lectin-Like Receptor Subfamily A - Abstract
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.
- Published
- 2010