Novel EXO-T vaccine using polyclonal CD4+ T cells armed with HER2-specific exosomes for HER2-positive breast cancer

Abstract

Breast cancer is the leading cause of death in women globally. The human epidermal growth factor receptor 2 (HER2)-positive breast cancer is often associated with poor prognosis and high mortality. Even though anti-HER2 monoclonal antibodies have improved the clinical outcome, resistance to the antibody therapy becomes a major obstacle in the treatment of HER2-positive breast cancer patients. Alternative approaches are therefore needed. HER2-specific vaccines have been developed to trigger patient's immune system against HER2-positive breast cancer. This article describes the development of novel HER2-specific exosome (EXO)-T vaccine using polyclonal CD4⁺ T cells armed with HER2-specific dendritic cell-released EXO and demonstrates its therapeutic effect against HER2-positive tumor in double-transgenic HER2/HLA-A2 mice with HER2-specific self-immune tolerance. Therefore, our novel HER2-specific EXO-T vaccines are likely to assist in the treatment of HER2-positive breast cancer patients.

Keywords: EXO-T vaccine; HER2; T cell; breast cancer; exosome; polyclonal CD4+.

Figure 1

Functional characteristics of the novel EXO-T vaccine. Notes: (A) Conventional three signals in APC-stimulated CD8+ T-cell responses, including 1) antigen peptide/major histocompatibility complex-I (pMHC-I)/TCR, 2) costimulatory CD80/CD28, and 3) cytokines IL-1α, IL-12 (for T-cell functional development), and IL-15 (for T-cell memory formation). (B) Distinct three signals derived from novel EXO-T vaccine include 1) exosomal pMHC-I/TCR, 2) exosomal CD80/CD28 and T-cell CD40L/CD40 (for T-cell memory formation), and 3) T-cell cytokine IL-2 (for T-cell proliferation). (C) Conversion of exhausted CD8⁺ CTLs within tumor by EXO-T cells via T cell CD40L/CD40-activated mTORC1 pathway. Abbreviations: APC, antigen-presenting cell; CTLs, cytotoxic T lymphocytes; EXO, exosome; IFN-γ, interferon-γ; TCR, T-cell receptor.