Abstract 1451: HER2 peptide pulsed dendritic cell vaccine induce senescence and eliminates disseminated cancer cells in a preventive model of transgenic HER2/neu breast cancer
Authors: Ganesan Ramamoorthi, Krithika Kodumudi, Colin Synder, William Dominguez-Viqueira, Scott Kidd, Shari Pilon-Thomas, Brian Czerniecki
Journal: Cancer Research (2019)

Abstract HER-2/neu overexpression plays a critical role in breast cancer development, and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. The detection of disseminated cancer cells (DCCs) in early-stage DCIS likely to become invasive and manifests prominent role in metastasis and recurrence. The HER2-positive DCCs can easily escape targeted therapies and become a source of tumor recurrence suggesting that targeting these cells may provide eminent benefits in HER2 positive breast cancer patients. Unfortunately, the conventional therapies that target these DCCs are limited. Previous studies from our lab have shown that HER2 peptide pulsed-DC1 (HER2-DC1) vaccine induced 30% complete response (pCR) in DCIS patients. However, little is known about the effect of HER2-DC1 vaccine on DCCs. Here, we investigated the efficacy of HER2-DC1 vaccine on DCCs in a transgenic HER2 mammary cancer model (neuT). The key features of this model are each one of ten mammary glands develops an independent carcinoma that slowly progresses from a microscopic lesion to an invasive tumor and metastasis is mainly driven by DCCs. Since this model mimics some of the most critical features of human disease, we evaluated the efficacy of HER2-DC1 vaccine on DCCs. Mice received six doses of HER2-DC1 vaccine subcutaneously twice a week. The spontaneous tumor development in the mammary glands of NeuT mice was examined once a week by ultrasound until the age of week 16. HER2-DC1 vaccine significantly prevented spontaneous tumor growth in NeuT mice. Remarkably, HER2-DC1 vaccine treatment significantly decreased HER2+CYT8/18+Ki-67+ proliferative DCCs (2%, p&amp;lt;0.002) in the bone marrow (BM-DCCs) compared to untreated mice (6%) by flow cytometry. We also observed increased senescent DCCs (82%, p&amp;lt;0.0001 compared to untreated mice, 37%) by a β-gal assay. BM-DCCs in HER2-DC1 vaccinated mice had reduced expression of Ki-67 compared to untreated mice. Multicolor flow cytometry demonstrated elevated levels of CD4 T cells (2 fold increase) and CD8 T cells (1 fold increase) in the bone marrow after HER2-DC1 vaccination compared to untreated mice. Importantly, accumulation of CD4 T cells (5 fold increase), CD8 T cells (19 fold increase) and B cells (100 fold increase) was observed in the mammary glands of HER2-DC1 vaccinated mice with strong anti-HER2 Th1 immune responses. Notably, HER2-DC1 vaccine led to an increased in the M1 macrophage phenotype (3 fold increase) and decreased M2 type (8 fold decrease) at the tumor site. Treatment of DCCs with Th1 cytokines, IFN-γ or TNF-α significantly induced senescence (76.3%, p&amp;lt;0.0001) in cultured DCCs compared to untreated cells (26%) in vitro. These results describe the novel role of HER2-DC1 vaccine in targeting DCCs and a possible role in prevention of metastasis and recurrence. Citation Format: Ganesan Ramamoorthi, Krithika Kodumudi, Colin Synder, William Dominguez-Viqueira, Scott Kidd, Shari Pilon-Thomas, Brian Czerniecki. HER2 peptide pulsed dendritic cell vaccine induce senescence and eliminates disseminated cancer cells in a preventive model of transgenic HER2/neu breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1451.