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Immunization against HIF-1? Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo.

ABSTRACT: Purpose: Triple-negative breast cancer (TNBC) represents a cancer stem cell-enriched phenotype. Hypoxia-inducible factor-1? (HIF-1?) induces the expression of proteins associated with stemness and is highly upregulated in TNBC. We questioned whether HIF-1? was immunogenic and whether vaccination targeting HIF-1? would impact the growth of basal-like mammary tumors in transgenic mice.Experimental Design: We evaluated HIF-1?-specific IgG in sera from controls and patients with breast cancer. Class II epitopes derived from the HIF-1? protein sequence were validated by ELISPOT. To assess therapeutic efficacy, we immunized Tg-MMTVneu and C3(1)Tag mice with HIF-1? Th1-inducing peptides. Stem cells were isolated via magnetic bead separation. Levels of HIF-1? and stem cells in the tumor were quantitated by Western blotting and flow cytometry.Results: The magnitude (P < 0.001) and incidence (P < 0.001) of HIF-1?-specific IgG were elevated in TNBC patients compared with controls. Both breast cancer patients and donors showed evidence of HIF-1?-specific Th1 and Th2 immunity. Three HIF-1?-specific Th1 class II restricted epitopes that were highly homologous between species elicited type I immunity in mice. After HIF-1? vaccination, mammary tumor growth was significantly inhibited in only C3(1)Tag (basal-like/stem cellhigh; P < 0.001) not TgMMTV-neu (luminal/neu/stem celllow; P = 0.859) murine models. Vaccination increased type I T cells in the tumor (P = 0.001) and decreased cells expressing the stem cell marker, Sca-1, compared with controls (P = 0.004).Conclusions: An HIF-1? vaccine may be uniquely effective in limiting tumor growth in TNBC. Inhibiting outgrowth of breast cancer stem cells via active immunization in the adjuvant setting may impact disease recurrence. Clin Cancer Res; 23(13); 3396-404. ©2016 AACR.

SUBMITTER: Cecil DL

PROVIDER: S-EPMC5493515 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo.

Cecil Denise L DL Slota Meredith M O'Meara Megan M MM Curtis Benjamin C BC Gad Ekram E Dang Yushe Y Herendeen Daniel D Rastetter Lauren L Disis Mary L ML

Clinical cancer research : an official journal of the American Association for Cancer Research 20161230 13

Purpose: Triple-negative breast cancer (TNBC) represents a cancer stem cell-enriched phenotype. Hypoxia-inducible factor-1α (HIF-1α) induces the expression of proteins associated with stemness and is highly upregulated in TNBC. We questioned whether HIF-1α was immunogenic and whether vaccination targeting HIF-1α would impact the growth of basal-like mammary tumors in transgenic mice.Experimental Design: We evaluated HIF-1α-specific IgG in sera from controls and patients with breast ...[more]

PMID: 28039264

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Project description:Alteration in glycosylation pattern of MUC1 mucin tandem repeats during carcinomas has been shown to negatively affect adhesive properties of malignant cells and enhance tumor invasiveness and metastasis. In addition, MUC1 overexpression is closely interrelated with angiogenesis, making it a great target for immunotherapy. Alongside, easier interaction of nanobodies (single-domain antibodies) with their antigens, compared to conventional antibodies, is usually associated with superior desirable results. Herein, we evaluated the preclinical efficacy of a recombinant nanobody against MUC1 tandem repeats in suppressing tumor growth, angiogenesis, invasion, and metastasis. Expressed nanobody demonstrated specificity only toward MUC1-overexpressing cancer cells and could internalize in cancer cell lines. The IC50 values (the concentration at which the nanobody exerted half of its maximal inhibitory effect) of the anti-MUC1 nanobody against MUC1-positive human cancer cell lines ranged from 1.2 to 14.3 nm. Similar concentrations could also effectively induce apoptosis in MUC1-positive cancer cells but not in normal cells or MUC1-negative human cancer cells. Immunohistochemical staining of spontaneously developed mouse breast tumors prior to in vivo studies confirmed cross-reactivity of nanobody with mouse MUC1 despite large structural dissimilarities between mouse and human MUC1 tandem repeats. In vivo, a dose of 3 µg nanobody per gram of body weight in tumor-bearing mice could attenuate tumor progression and suppress excessive circulating levels of IL-1a, IL-2, IL-10, IL-12, and IL-17A pro-inflammatory cytokines. Also, a significant decline in expression of Ki-67, MMP9, and VEGFR2 biomarkers, as well as vasculogenesis, was evident in immunohistochemically stained tumor sections of anti-MUC1 nanobody-treated mice. In conclusion, the anti-MUC1 tandem repeat nanobody of the present study could effectively overcome tumor growth, invasion, and metastasis.

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Immunization against HIF-1? Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo.

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Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells <i>In Vivo</i>.

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