Plasmacytoid Dendritic Cells and Cancer Immunotherapy

Abstract

Despite largely disappointing clinical trials of dendritic cell (DC)-based vaccines, recent studies have shown that DC-mediated cross-priming plays a critical role in generating anti-tumor CD8 T cell immunity and regulating anti-tumor efficacy of immunotherapies. These new findings thus support further development and refinement of DC-based vaccines as mono-immunotherapy or combinational immunotherapies. One exciting development is recent clinical studies with naturally circulating DCs including plasmacytoid DCs (pDCs). pDC vaccines were particularly intriguing, as pDCs are generally presumed to play a negative role in regulating T cell responses in tumors. Similarly, DC-derived exosomes (DCexos) have been heralded as cell-free therapeutic cancer vaccines that are potentially superior to DC vaccines in overcoming tumor-mediated immunosuppression, although DCexo clinical trials have not led to expected clinical outcomes. Using a pDC-targeted vaccine model, we have recently reported that pDCs required type 1 conventional DCs (cDC1s) for optimal cross-priming by transferring antigens through pDC-derived exosomes (pDCexos), which also cross-prime CD8 T cells in a bystander cDC-dependent manner. Thus, pDCexos could combine the advantages of both cDC1s and pDCs as cancer vaccines to achieve better anti-tumor efficacy. In this review, we will focus on the pDC-based cancer vaccines and discuss potential clinical application of pDCexos in cancer immunotherapy.

Immune-Cell-Derived Exosomes for Cancer Therapy

“…As the most effective antigen-presenting cells (APCs), DCs play an essential role in initiating persistent innate and adaptive immunity and are of great significance in the body’s immune function and tumor immune management. , DC-derived exosomes are tiny vesicles secreted by sentinel APCs of the immune system, carrying DC antigens such as functional MHC-antigenic complexes and T cells costimulatory molecules, which participate in specific cytotoxic T lymphocyte (CTL) responses to inhibit tumor growth. , Tumor-infiltrating DCs can convey tumor-related antigens to effector T cells, promote memory T cells to induce differentiation, enhance the therapeutic effects of immune checkpoint inhibitors, and finally prevent recurrence of tumors. , Recently, considerable emphasis has been paid to the role of DC-derived exosomes in tumor immunity, and the clinical trials based on DC-derived exosomes have proven their potential practicality in cancer therapy. , Indeed, the tumor-peptide-pulsed DC-derived exosomes have been used as antitumor vaccines to treat cancers and show encouraging efficacy in the preclinical trials. , …”

“…69,70 Recently, considerable emphasis has been paid to the role of DC-derived exosomes in tumor immunity, and the clinical trials based on DC-derived exosomes have proven their potential practicality in cancer therapy. 71,72 Indeed, the tumor-peptide-pulsed DCderived exosomes have been used as antitumor vaccines to treat cancers and show encouraging efficacy in the preclinical trials. 73,74 Viaud et al originally reported that DC-derived exosomes transferred functional MHC-antigenic complexes (classes I and II) to DCs and promoted the activation of CD8 + and CD4 + T cells, respectively (Figure 4A,B).…”

The Impact of Infused Autograft Absolute Numbers of Immune Effector Cells on Survival Post-Autologous Stem Cell Transplantation

“…Among the professional antigen-presenting cells are dendritic cells. Dendritic cells are divided into dendritic cells type 1 (DC1) and type 2 (DC2) [ 23 ]. DC1 express CD11 and have a myeloid morphology.…”

“…DC1 express CD11 and have a myeloid morphology. When DC1 are stimulated by tumor necrosis factor, DC1 produce high levels of interleukin 12 (IL-12) causing antigen-naïve CD4 to differentiate into T helper type 1 cells [ 23 ]. T helper type 1 cells secret interferon-gamma and tumor necrosis factor-alpha leading to the activation and development of cytotoxic T cells.…”

“…Furthermore, activated DC1 can directly kill tumor cells through tumor necrosis factor-related apoptosis-including ligand (TRAIL) and Granzyme B-dependent mechanisms causing tumor regression [ 26 ]. In contrast, DC2 has been associated with the differentiation of antigen-naïve CD4 into T helper type 2 cells, leading to a more pro-inflammatory microenvironment and immunosuppression [ 23 ]. Dean et al initially reported better survival in patients with higher numbers of collected and infused autograft-dendritic cells (A-DC) [ 27 ].…”