Plasmacytoid Dendritic Cells and Cancer Immunotherapy.

Chunmei Fu,Aimin Jiang,Li Zhou,Qing-Sheng Mi

doi:10.3390/cells11020222

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.

Highlights

As the sentinel of the immune system, dendritic cell (DC) play a critical role in mediating both innate and adaptive immune responses [1]
Developing from common myeloid progenitors (CMPs), macrophage/DC progenitors (MDPs) give rise to a population referred to as the common DC progenitors (CDPs), which in turn differentiate into two major DC subsets: classical DCs (cDCs) and plasmacytoid DCs (pDCs) [4,6,7,8,10,11]. cDCs can be further divided into two major subtypes, currently described as cDC1s and cDC2s that differ in their function, phenotypes, and transcriptional factor dependency. cDC1s depend on interferon regulatory factor 8 (IRF8) and basic leucine zipper transcriptional factor ATF-like 3 (Batf3) for their development, and are identified as XCR1hi CD24hi CD26hi
A recent study has shown that while BDCA1+ cDC2s are better at inducing antigen-specific CD8 T cell responses, pDCs are more efficient in activating NK cells [121]

Summary

Introduction

As the sentinel of the immune system, DCs play a critical role in mediating both innate and adaptive immune responses [1]. Activated pDCs induced anti-tumor CD8 T cell responses after systemic RNA delivery, whether this response is a result of antigen presentation by pDCs or is due to IFN-I-mediated activation of cDCs remains unclear [67] Further complicating this issue, recent studies have shown that isolated population of pDCs used in functional studies often contain transitional pDCs that are related to both pDCs and cDCs. From human blood, BM and tonsil, a subset of CD2+ CD5+ CD81+ DCs that express multiple pDC markers (CD123, CD303, CD304) were identified, and they produced. That both human and murine pDCs have been shown to be capable of directly killing tumor cells through granzyme B- and/or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent mechanisms [95,96,97,98] (Table 1)

Current pDC-Based Cancer Vaccine Clinical Trials

Phase I Clinical Trials for pDC Cancer Vaccines

Phase II Clinical Trial for pDC Cancer Vaccines

Would Plasmacytoid DC-Derived Exosomes Be Used as Cancer Vaccines?

Findings

Conclusions and Future Perspectives