Dendritic Cell–Based Vaccines that Utilize Myeloid Rather than Plasmacytoid Cells Offer a Superior Survival Advantage in Malignant Glioma

Abstract

Dendritic cells (DC) are professional antigen presenting cells (APC) that are traditionally divided into two distinct subsets: myeloid DC (mDCs) and plasmacytoid DC (pDCs). pDCs are known for their ability to secrete large amount of IFN-α. Apart from IFN-α production, pDCs can also process antigen and induce T-cell immunity or tolerance. In several solid tumors, pDCs have been shown to play a critical role in promoting tumor immunosuppression. We investigated the role of pDCs in the process of glioma progression in the syngeneic murine model of glioma. We show that glioma-infiltrating pDCs are the major APC in glioma and are deficient in IFN-α secretion (p < 0.05). pDC depletion leads to increased survival of the mice bearing intracranial tumor by decreasing the number of regulatory T-cells (Treg) and by decreasing the suppressive capabilities of Tregs. We subsequently compared the ability of mDCs and pDCs to generate effective anti-glioma immunity in a GL261-OVA mouse model of glioma. Our data suggest that mature pDCs and mDCs isolated from naïve mice can be effectively activated and loaded with SIINFEKL antigen in vitro. Upon intra-dermal injection in the hind leg, a fraction of both types of DCs migrate to the brain and lymph nodes.. Compared to mice vaccinated with pDC or control mice, mice vaccinated with mDCs generated a robust Th1 type immune response, characterized by high frequency of CD4+Tbet+ T-cells and CD8+Siinfekel+ T-cells. This robust anti-tumor T-cell response resulted in tumor eradication and long-term survival in 60% of the animals (p<0.001).

Engineering challenges for brain tumor immunotherapy

“…Dendritic cells (DCs) are also found in the brain tumor microenvironment, yet their immune function is typically stunted [41–43]. Normal DCs secrete IFNα leading to T-cell maturation, while brain tumor associated DCs elicit no IFNα secretion [43].…”

“…Normal DCs secrete IFNα leading to T-cell maturation, while brain tumor associated DCs elicit no IFNα secretion [43]. The increased VEGF concentrations in and around brain tumors, not only aids in recruitment of monocytes to the tumor, but is also known to disrupt DC and monocyte maturation [38,44].…”

Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer

“…While TLR9 and TLR7 have consistently been detected in murine plasmacytoid (pDCs) (Dey et al 2015;Swiecki and Colonna 2015) and conventional DCs (Degli-Esposti and Smyth 2005), the expression of these receptors in human DC compartments remains unclear. Whereas there is consensus over the expression of TLR9 and TLR7 in human pDCs, their expression in human conventional DCs has been reported either as null (Hemont et al 2013;Jarrossay et al 2001), weak (Bauer et al 2001;Hornung et al 2002;Meixlsperger et al 2013) or high (Hoene et al 2006;Ito et al 2002).…”

A concise review of immunotherapy for glioblastoma

“…These professional APCs have been judiciously utilized for GB management since they are appealing candidates for therapeutic exploitation. DCs can be categorized into myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) [62,63] . In the study by Dey et al [63] , mice vaccinated with mDCs generated an improved antitumor T cell response compared to pDC vaccinated mice.…”

“…DCs can be categorized into myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) [62,63] . In the study by Dey et al [63] , mice vaccinated with mDCs generated an improved antitumor T cell response compared to pDC vaccinated mice. The use of DC-based vaccines achieved impressive results for newly diagnosed GB patients [61] .…”