Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo.
Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo.
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DOI：
10.1158/1078-0432.ccr-16-1678
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发表时间：
2017-07-01
期刊：
影响因子：
--
通讯作者：
Disis ML
中科院分区：
文献类型：
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作者：
Cecil DL;Slota M;O'Meara MM;Curtis BC;Gad E;Dang Y;Herendeen D;Rastetter L;Disis ML
三阴性乳腺癌（TNBC）代表癌症干细胞富集表型。缺氧诱导因子-1 α（HIF-1α）诱导与干性相关的蛋白质的表达，并在TNBC中高度上调。我们质疑HIF-1α是否具有免疫原性，以及靶向HIF-1α的疫苗接种是否会影响转基因小鼠基底样乳腺肿瘤的生长。我们评估了对照组和乳腺癌患者血清中HIF-1α特异性IgG。通过ELISPOT验证源自HIF-1α蛋白序列的II类表位。为了评估治疗效果，我们用HIF-1α Th 1诱导肽免疫Tg-MMTVneu和C3（1）Tag小鼠。通过磁珠分离分离干细胞。采用Western blotting和流式细胞术检测肿瘤中HIF-1α和干细胞的水平。与对照组相比，TNBC患者中HIF-1α特异性IgG的幅度（p<0.001）和发生率（p<0.001）升高。乳腺癌患者和供体均显示HIF-1α特异性辅助性T细胞（Th）1和Th 2免疫。3个种属间高度同源的HIF-1α特异性Th 1 Ⅱ类限制性表位可诱导小鼠产生Ⅰ型免疫。HIF-1α疫苗接种后，乳腺肿瘤生长仅在C3（1）Tag（基底细胞样/干细胞高）（p<0.001）而非TgMMTV-neu（管腔/neu/干细胞低）（p=0.859）小鼠模型中受到显著抑制。与对照组相比，疫苗接种增加了肿瘤中的I型T细胞（p=0.001），并减少了表达干细胞标志物Sca-1的细胞（p=0.004）。HIF-1α疫苗可能在限制TNBC肿瘤生长方面具有独特的有效性。通过在辅助环境中主动免疫抑制乳腺癌干细胞的生长可能会影响疾病复发。
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. 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. 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). 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.