DC-Based Vaccines for Cancer Immunotherapy

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.

Exosome-Based Vaccines: History, Current State, and Clinical Trials

“…DEXs also possess more peptide-MHC I and -MHC II complexes than DCs, thereby rendering the use of DEXs a less time-and space-consuming strategy (Figure 2A) (66)(67)(68). Additionally, DEXs are more resistant to immunosuppressive mechanisms in the tumor microenvironment than DCs (69). Exosomes are reportedly more capable of inducing immunocompetence in DCs than in microvesicles.…”

“…According to Fu and colleagues, the lack of an immune response to these vaccines can be associated with the DC type selected by researchers in these clinical trials (69). They used immature DCs, while other studies showed that exosomes derived from mature DCs induced more potent T-cell priming.…”

An Update on the HIV DNA Vaccine Strategy

“…This nanobody technology has proven successful at targeting lentiviral vectors to murine DCs both in vitro and in situ and has previously been discussed [75,76]. Further, because of their ability to mediate host effector and memory CD8+ T cell responses, which is crucial for anti-tumor immunity, DC-based vaccines have become one of the leading strategies for cancer immunotherapy [77]. However, in the case of therapeutic HIV vaccines, vector-transduced DCs can themselves act as latency-reversing agents (LRAs) by secreting high levels of cytokines, such as TNF-α, and they are also capable of homing to lymphoid tissues where latently-infected viral reservoirs reside to potentially activate latent viral reservoirs.…”

Cancer immunotherapy: A comprehensive appraisal of its modes of application (Review)

“…The advantages of DC vaccines include their personalized nature, the feasibility of producing an immune response since dendritic cells are major players in the activation of adaptive responses, their ability to specify the response towards one antigen or a group of antigens and the relatively safety in individuals as they do not cause AEs (108). By contrast, DC-based vaccines, similar to other vaccines, face certain hurdles, such as tumor immunosuppression and the limited functions of monocyte-derived dendritic cells, which are the cells used to generate this type of vaccines (109). In addition, since they are personalized, DC vaccines tend to be expensive (109).…”

“…By contrast, DC-based vaccines, similar to other vaccines, face certain hurdles, such as tumor immunosuppression and the limited functions of monocyte-derived dendritic cells, which are the cells used to generate this type of vaccines (109). In addition, since they are personalized, DC vaccines tend to be expensive (109). As with other types of vaccines, DC vaccines suppress tumor growth and increase the number of T cells infiltrating the tumor microenvironment, which can be more efficient compared with other types of vaccines in certain cases, such as in murine lung carcinoma (LL2), the study was done in vitro and the DC vaccine was able to exhibit superior immunogenicity compared with an antigen-adjuvant vaccine (102).…”