Immunization against HIF-1α inhibits the growth of basal mammary tumors and targets mammary stem cells in vivo.

Publication Type:

Journal Article

Source:

Clinical cancer research : an official journal of the American Association for Cancer Research (2016)

Abstract:

PURPOSE: Triple negative breast cancer (TNBC) represents a cancer stem cell enriched phenotype. Hypoxia-inducible factor-1 alpha (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 cancer. Class II epitopes derived from the HIF-1α protein sequence were validated by ELISPOT. To assess therapeutic efficacy, we immunized Tg-MMTVneu and C3(1)Tag mice with HIF-1α Th1-inducing peptides. Stem cells were isolated via magnetic bead separation. Levels of HIF-1α 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-1α-specific IgG was elevated in TNBC patients compared to controls. Both breast cancer patients and donors showed evidence of HIF-1α-specific T-helper (Th) 1 and Th2 immunity. Three HIF-1α-specific Th1 class II restricted epitopes that were highly homologous between species elicited Type I immunity in mice. After HIF-1α 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 cell low) (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 to controls (p=0.004).

CONCLUSIONS: A HIF-1α 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.