Abstract
As the sentinels of the immune system, dendritic cells (DCs) play a critical role in initiating and regulating antigen-specific immune responses. Cross-priming, a process that DCs activate CD8 T cells by cross-presenting exogenous antigens onto their MHCI (Major Histocompatibility Complex class I), plays a critical role in mediating CD8 T cell immunity as well as tolerance. Current DC vaccines have remained largely unsuccessful despite their ability to potentiate both effector and memory CD8 T cell responses. There are two major hurdles for the success of DC-based vaccines: tumor-mediated immunosuppression and the functional limitation of the commonly used monocyte-derived dendritic cells (MoDCs). Due to their resistance to tumor-mediated suppression as inert vesicles, DC-derived exosomes (DCexos) have garnered much interest as cell-free therapeutic agents. However, current DCexo clinical trials have shown limited clinical benefits and failed to generate antigen-specific T cell responses. Another exciting development is the use of naturally circulating DCs instead of in vitro cultured DCs, as clinical trials with both human blood cDC2s (type 2 conventional DCs) and plasmacytoid DCs (pDCs) have shown promising results. pDC vaccines were particularly encouraging, especially in light of promising data from a recent clinical trial using a human pDC cell line, despite pDCs being considered tolerogenic and playing a suppressive role in tumors. However, how pDCs generate anti-tumor CD8 T cell immunity remains poorly understood, thus hindering their clinical advance. Using a pDC-targeted vaccine model, we have recently reported that while pDC-targeted vaccines led to strong cross-priming and durable CD8 T cell immunity, cross-presenting pDCs required cDCs to achieve cross-priming in vivo by transferring antigens to cDCs. Antigen transfer from pDCs to bystander cDCs was mediated by pDC-derived exosomes (pDCexos), which similarly required cDCs for cross-priming of antigen-specific CD8 T cells. pDCexos thus represent a new addition in our arsenal of DC-based cancer vaccines that would potentially combine the advantage of pDCs and DCexos.
Highlights
As the professional antigen presenting cells (APCs), dendritic cells (DCs) play a critical role in the initiation and regulation of innate and adaptive immune responses, and have the unique ability to activate both naïve CD4 and CD8 T cells [1]
B cell vaccines represent an attractive alternative to DC vaccines, as B cell function in T cell activation has been shown to be resistant to immunosuppressive cytokines including IL-10, TGF-β and VEGF often present in the tumor microenvironment [12,13]
More resistant to tumor-mediated suppression compared to DCs, superior biostability, and the potential of using plasmacytoid DCs (pDCs) cell lines further improves bioavailability and lowers cost pDC-derived exosomes (pDCexos) were only reported recently, further characterization of these pDCexos and pre-clinical and clinical data are required to assess their potential as cancer vaccines
Summary
As the professional antigen presenting cells (APCs), dendritic cells (DCs) play a critical role in the initiation and regulation of innate and adaptive immune responses, and have the unique ability to activate (prime) both naïve CD4 and CD8 T cells [1]. B cell vaccines represent an attractive alternative to DC vaccines, as B cell function in T cell activation has been shown to be resistant to immunosuppressive cytokines including IL-10, TGF-β and VEGF often present in the tumor microenvironment [12,13]. Vaccines with these other APCs are under-studied, and DCs remain the overwhelming cell of choice for cell-based vaccines for cancer immunotherapy [14]. The generation of previously unreported pDC-derived exosomes (pDCexos) [31] offer an exciting new addition in the arsenal of DC-based vaccines, as vaccines with pDCexos have the potential to combine the advantages of both pDC and DCexo vaccines
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