1556 - Retinoid X receptor agonists enhances Th1 antigen-specific and polyfunctional T cells with the HER2-IGFBP2-IGF1R vaccine

Document Type

Presentation

Publication Date

4-10-2021

Publication Title

AACR Annual Meeting

Keywords

oregon; portland; ppmc; chiles

Abstract

Bexarotene and 9cUAB30 are highly selective oral retinoid X receptor (RXR) agonists with anti-proliferative activity in breast cancer. We have demonstrated that bexarotene enhances efficacy of a multi-antigen vaccine to prevent breast cancer in the TgMMTV-neu model and increases CD8 T-cell tumor infiltration. We further have shown that RXRα expression is in 24.9±13% of macrophages, 38.6 ±14% of plasmacytic dendritic cells (pDC), and 33.1 ± 16% of monocytic dendritic cells (mDC). Furthermore, the RXR agonists increased Th1 pDC and mDC. We therefore evaluated whether RXR agonists could enhance the vaccine antigen-specific immunogenicity and polyfunctional T cells in the transgenic mouse mammary tumor model TgMMTV-neu. Vaccination with the 150 µg HER2-IGFBP2-IGF1R vaccine and 5 ug GMCSF adjuvant every 2 weeks for four doses significantly increased antigen-specific IFN-γ T cells, but not antigen-specific IL10 T cells, as compared to control vaccination with empty vector. Interestingly, daily oral administration of 30 mg/kg bexarotene for 5 days prior to the HER2-IGFBP2-IGF1R vaccination series increased the IFN-γ immune responses to HER2, IGFBP2, and IGF1R by 1.2, 2.4 and 2.2 fold, respectively, as compared to the HER2-IGFBP2-IGF1R vaccine alone. Daily administration of a higher dose (200 mg/kg) 9cUAB30 for 5 days prior to the HER2-IGFBP2-IGF1R vaccination series increased the IFN-γ immune responses to HER2, IGFBP2, and IGF1R by 2.0, 2.3 and 1.7 fold, respectively, as compared to the HER2-IGFBP2-IGF1R vaccine alone. Control vaccination with either 9cUAB30 or bexarotene had no impact on antigen-specific IFN-γ T cell response. Type I DCs are important for producing polyfunctional CD4+ T cells that release not only IFN-γ but also TNF-α and IL-2. Polyfunctional T cells induce a longer lasting and more effective immune response in vaccines both for infectious diseases and cancer. We demonstrated the addition of bexarotene or 9cUAB30 increased antigen-specific polyfunctional T cells in the TgMMTV-neu (n=15 mice) transgenic mouse mammary tumor model while vaccination alone did not. There were an average of 1.3±0.2% antigen-specific CD4 polyfunctional T cells and 2.7±0.7 antigen-specific CD8 polyfunctional T cells with empty vector and vehicle control (sesame oil). HER2-IGFBP2-IGF1R vaccination following 30 mg/kg bexarotene treatment increased polyfunctional T cells to an average of 6.1±2.0% antigen-specific CD4 polyfunctional T cells (p=0.07) and 20.3±4.1% antigen-specific CD8 polyfunctional T cells (p=0.0003). HER2-IGBP2-IGF1R vaccination after 200 mg/kg 9cUAB30 increased antigen-specific polyfunctional T cells to 7.6±2.0% (p=0.01) and antigen-specific CD8 polyfunctional T cells to 17.6±4.1% (p=0.003). These data indicate that RXR agonists have an immunostimulatory role with multi-antigen cancer vaccines and may augment the anti-tumor activity of vaccines.

Clinical Institute

Cancer

Department

Earle A. Chiles Research Institute

Department

Oncology

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