Tumorantigen-Specific CD40B Cells: Combining Enhanced Antigen-Presentation and Antibody-Secretion for Tumor Targeting

Abstract

Efficient antigen presentation is a prerequisite for the development of a T-cell-mediated immune response. Dendritic cells (DCs) are the most prominent professional antigen-presenting cells (APCs). However, they have several disadvantages as cellular adjuvant in cancer immunotherapy. Therefore, an alternative approach was developed, in which polyclonal B cells can serve as potent APCs by treatment with the CD40 ligand. We demonstrated that CD40-activation dramatically improves antigen presentation by B cells, efficiently inducing naive and memory CD4+ and CD8+ T-cell responses. Moreover, these CD40-activated (CD40) B cells home to secondary lymphoid organs. However, antigen presentation by antigen-specific B cells is more effective compared to polyclonal B cells. Therefore, we use tumorantigen-specific B cells to improve the antigen-presenting function of CD40B cells. Purified human and murine tumorantigen-specific B cells highly upregulate activation markers upon CD40-stimulation, which results in an enhanced CD4+ and CD8+ T cell response in vitro and in vivo. This response is significantly lower in polyclonal CD40B cells and comparable to the stimulation induced by mature dendritic cells. Moreover, antigen-specific B cells could be stimulated in vitro to differentiate into antibody-secreting plasma cells. Treatment of E.G7 lymphoma-bearing mice with a combination of antigen-specific CD40B cells and plasma cells results in inhibition of tumor growth and prolonged survival. Moreover, antigen-specific B cells home to the tumor site and the spleen, where they encounter T cells. These results provide new insights into the role of activated antigen-specific B cells as APCs and their use for cancer immunotherapy. DisclosuresScheid:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.