Vaccination with ErbB-2 peptides prevents cancer stem cell expansion and suppresses the development of spontaneous tumors in MMTV-PyMT transgenic mice

Abstract

ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low. Here, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant. ErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells. We provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.

Natural and therapy-induced immunosurveillance in breast cancer

“…In addition, the neutralization of IFN-γ, HMGB1 or interferon (α, β and Ω) receptor 1 (IFNAR1), as well as the knockout of myeloid differentiation primary response gene 88 (Myd88), which encodes a signal transducer operating downstream of many Toll-like receptors, abrogates the therapeutic efficacy of anti-ERBB2 mAbs in mouse models of BC 103,104 , indicating that trastuzumab may also promote ICD. In fact, preclinical data suggest that the induction of CTL-dependent immune responses against ERBB2 might constitute a valuable therapeutic goal 105 . A phase 1/2 clinical study concluded that the HLA-A2 + BC patients immunized with a peptide derived from ERBB2 and granulocyte-macrophage colony-stimulating-factor (GM-CSF) exhibit an improved 5-year disease-free survival as compared to HLA-A2 -patients treated with GM-CSF only 106 .…”

Identifying network biomarkers based on protein-protein interactions and expression data

“…Moreover, for dataset GSE10797 in a four-class case, we also found some evidence with the help of KEGG pathway search, we found that several pathways are statistically significant, e.g., hsadd05200 Pathways in cancer, hsa04012 ErbB signaling pathway and hsadd04510 Focal adhesion pathway. ErbB-2 is a target for cancer-initiating cells in breast and other cancers [ 28 ]. Amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in HER2-positive breast cancer [ 29 ].…”

Immune responses to human cancer stem‐like cells/cancer‐initiating cells

“…Sphere‐forming GBM stem cells showed higher susceptibility to CTL than did NK cells . HER2‐specific peptide vaccination decreased aldehyde dehydrogenase (ALDH)‐positive breast cancer stem cells in MMTV‐PyMT transgenic breast cancer model mice . All of these observations in humans and mice suggest that treatment‐resistant CSC/CIC are sensitive to differentiated CTL both in vitro and in vivo .…”