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. 2008 May;57(5):655-62.
doi: 10.1007/s00262-007-0404-2. Epub 2007 Sep 22.

Ly49G2 receptor blockade reduces tumor burden in a leukemia model but not in a solid tumor model

Melissa A Barber  1 , Tong Zhang, Bethany A Gagne, Jo A Van Ginderachter, Patrick De Baetselier, Charles L Sentman
Affiliations

Ly49G2 receptor blockade reduces tumor burden in a leukemia model but not in a solid tumor model

Melissa A Barber et al. Cancer Immunol Immunother. 2008 May.

Abstract

Background: NK cell activity is regulated in part by inhibitory receptors that bind to MHC class I molecules. It is possible to enhance NK cell cytotoxicity against tumor cells by preventing the interaction of these inhibitory receptors with their MHC class I ligands.

Results: In this study, we determined that Ly49G2 is an inhibitory receptor in AKR mice for self-MHC class I, and AKR Ly49G2 has an identical sequence to BALB/c Ly49G2. Blockade of Ly49G2 receptors in vivo resulted in decreased growth of BW-Sp3 lymphoma cells when the tumor cells were given i.v. but not when the tumor cells were inoculated into the flank forming a solid tumor. However, NK cells were involved in inhibiting the growth of BW-Sp3 tumor cells in the flank.

Conclusion: These data demonstrate that the effectiveness of inhibitory receptor blockade depends upon the tissue location of the tumor cells.

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Figures

Fig. 1
Fig. 1
Expression and sequence analysis of AKR Ly49G2. Expression of Ly49G2 is shown on flow cytometry plots of DX5+, CD3− cells from fresh AKR spleen cells (a) or 5-day rIL-2-activated AKR splenic NK cells (b). Ly49G2 was detected using anti-Ly49G2 (4D11). RT-PCR was performed using Ly49G2 consensus primers on AKR spleen cells. The cDNA (c) and predicted protein (d) sequences were compared to BALB/c, 129/J, and C57BL/6 (B6) sequences. Boxes in c and d indicate the critical nucleotides and amino acids, respectively, for ligand binding [40]. Locations of non-identity between the sequences are shown by underlining
Fig. 2
Fig. 2
Ly49G2 blocking enhances BW-Sp3 tumor cell lysis by AKR Ly49G2+ NK cells. DX5+ cells purified from the spleens of AKR mice and grown in complete media with 1,000 U/ml IL-2 for 5 days were separated into Ly49G2+ and Ly49G2− populations. Two days later, they were used as effectors in a chromium-release cytotoxicity assay against BW-Sp3 and BWO target cells. Anti-Ly49G2 (4D11) F(ab′)2 (open diamonds) or anti-Ly49C/I (5E6) F(ab′)2 (closed diamonds) fragments were included in wells, with PBS (open triangles) serving as a control. Percent specific lysis is shown, and data are representative of two independent experiments. Error bars represent SEM
Fig. 3
Fig. 3
BW-Sp3 tumor cells express H-2Dk and H-2Kk MHC class I molecules. BW-Sp3 tumor cells were analyzed for expression of H-2Dk and H-2Kk molecules (solid lines). Isotype control staining is shown (dotted lines)
Fig. 4
Fig. 4
NK cell-depletion but not Ly49G2 receptor blockade affects BW-Sp3 subcutaneous tumor growth. a Mice were given 2 × 106 BW-Sp3 tumor cells s.c. on day 0. Mice received anti-asialoGM1 sera (open symbols) or control rabbit sera (closed symbols) i.p. on days −1, +4, and +9. b AKR mice were inoculated with 2 × 106 BW-Sp3 cells s.c. and were treated with anti-Ly49G2 (4D11) F(ab′)2 (open diamonds) or control rat IgG F(ab′)2 (closed diamonds) beginning at day 0. A representative of three or four independent experiments is shown. Error bars represent SEM
Fig. 5
Fig. 5
Anti-Ly49G2 F(ab′)2 treatment reduces tumor burden of BW-Sp3/GFP tumor cells inoculated i.v. AKR mice were given 5 × 106 BW-Sp3/GFP cells i.v. on day 0. Anti-Ly49G2 (4D11) F(ab′)2 (open symbols) or control rat IgG F(ab′)2 (closed symbols), were injected i.p., every other day from day 0, for 7 days. Mice (n = 7/group/experiment) were sacrificed on day 17, and the percentage and number of GFP+ cells in bone marrow was determined by flow cytometry. Error bars represent SEM. Results are expressed relative to control-treated mice (=100%). The control-treated mice averaged 6.7% GFP+ cells and 3.6 × 105 GFP+ cells in the bone marrow. Data are combined from two independent experiments
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