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. 2007 Jun;9(6):487-94.
doi: 10.1593/neo.07259.

Antibodies to placental immunoregulatory ferritin with transfer of polyclonal lymphocytes arrest MCF-7 human breast cancer growth in a nude mouse model

Marisa Halpern  1 , Muayad A Zahalka, Leonid Traub, Chaya Moroz
Affiliations

Antibodies to placental immunoregulatory ferritin with transfer of polyclonal lymphocytes arrest MCF-7 human breast cancer growth in a nude mouse model

Marisa Halpern et al. Neoplasia. 2007 Jun.

Abstract

The recently cloned human gene named "placental immunoregulatory ferritin" (PLIF) is a pregnancy-related immunomodulator. Recombinant PLIF and its bioactive domain C48 are immune-suppressive and induce pronounced IL-10 production by immune cells. PLIF is expressed in the placenta and breast cancer cells. Blocking PLIF in pregnant mice by anti-C48 antibodies inhibited placental and fetal growth and modulated the cytokine network. It has been revealed that anti-C48 treatment inhibited MCF-7 tumor growth in nude mice. However, this significant effect was observed only in those transfused with human peripheral blood mononuclear cells. Blocking PLIF in tumor-engrafted human immune cell transfused mice resulted in massive infiltration of human CD45+ cells (mainly CD8+ T cells), both intratumorally and in the tumor periphery, and a significant number of caspase-3+ cells. In vitro, anti-C48 treatment of MCF-7 tumor cells cocultured with human lymphocytes induced a significant increase in interferon-gamma secretion. We conclude that blocking PLIF inhibits breast cancer growth, possibly by an effect on the cytokine network in immune cells and on breakdown of immunosuppression.

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Figures

Figure 1
Figure 1
The effect of anti-C48 Ig treatment without and with inoculated PBMC on the growth of MCF-7 breast tumors in nude mice. (a) Nude mice without PBMC inoculation. (b) Nude mice inoculated intravenously with human PBMCs (40 x 106/0.5 ml) (HICT) after the engraftment of MCF-7 breast cancer cells. All mice received daily intraperitoneal injections of anti-C48 Ig or control Ig (2 mg/0.3 ml). Bars represent mean ± S.E. (n = 6).
Figure 2
Figure 2
Gross and microscopic immunohistochemical analyses of tumors removed from HICT mice treated with anti-C48 Ig (A2, C, E, and G) or control Ig (A1, B, D, and F). (A) Tumor size. (B and C) CD45+ inside tumors. (D and E) CD45+ in tumors. (F and G) Caspase-3+.
Figure 3
Figure 3
The effect of anti-C48 Ig treatment on the survival of MCF-7 tumor-bearing HICT nude mice. Mice engrafted as in Figure 1 were treated daily (1–30 days) with anti-C48 Ig or control Ig (2 mg/0.3 ml, i.p.) and followed up for 45 days.
Figure 4
Figure 4
Quantitative immunohistochemical analysis of human leukocytes (CD45+) infiltrating MCF-7 human breast tumors removed from HICT nude mice treated with anti-C48 Ig and control Ig. Data are expressed as the mean percentage of positive cells in area section (4 mm2) ± S.E. (n = 3) (as in Materials and Methods).
Figure 5
Figure 5
Quantitative immunohistochemical analysis of human CD4 and CD8 T cells infiltrating human breast tumors removed from HITC nude mice treated with anti-C48 Ig and control Ig. Data are expressed as the mean proportion of CD45+ cells in area section (4 mm2) ± S.E. (n = 3).
Figure 6
Figure 6
Quantitative immunohistochemical analysis of caspase-3+ cells in human breast tumors removed from HITC nude mice treated with anti-C48 Ig and control Ig. Data are expressed as the mean percentage of positive cells in area (4 mm2) ± S.E. (n = 3).
Figure 7
Figure 7
Time course secretion of INF-γ in mixed cultures of MCF-7 cells and PBMCs (2 x 106 ml-1) treated daily with anti-C48 Ig or control Ig (100 µl). Culture supernatants were removed at 24, 48, and 72 hours of incubation and centrifuged at 500g for 10 minutes to remove cells and debris, and the supernatant (100 µg/ml) was subjected to an ELISA plate for quantitative measurement of INF-γ (a representative experiment).
Figure 8
Figure 8
Time course secretion of IL-10 in mixed cultures of MCF-7 cells and PBMCs (106 ml-1) treated daily with anti-C48 Ig or control Ig (100 µg/ml). Supernatants were collected as in Figure 7 and subjected (100 µl) to an ELISA plate for quantitative measurement of IL-10 (a representative experiment).
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