Optimized dendritic cell vaccination induces potent CD8 T cell responses and anti-tumor effects in transgenic mouse melanoma models

Abstract

Despite melanoma immunogenicity and remarkable therapeutic effects of negative immune checkpoint inhibitors, a significant fraction of patients does not respond to current treatments. This could be due to limitations in tumor immunogenicity and profound immunosuppression in the melanoma microenvironment. Moreover, insufficient tumor antigen processing and presentation by dendritic cells (DC) may hamper the development of tumor-specific T cells. Using two genetically engineered mouse melanoma models ( and transgenic mice), in which checkpoint inhibitor therapy alone is not efficacious, we performed proof-of-concept studies with an improved, multivalent DC vaccination strategy based on our recently developed genetic mRNA cancer vaccines. The expression of multiple chimeric MHC class I receptors allows a simultaneous presentation of several melanoma-associated shared antigens tyrosinase related protein (TRP)-1, tyrosinase, human glycoprotein 100 and TRP-2. The DC vaccine induced a significantly improved survival in both transgenic mouse models. Vaccinated melanoma-bearing mice displayed an increased CD8 T cell reactivity indicated by a higher IFN-γ production and an upregulation of activation marker expression along with an attenuated immunosuppressive pattern of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg). The combination of DC vaccination with ultra-low doses of paclitaxel or anti-PD-1 antibodies resulted in further prolongation of mouse survival associated with a stronger reduction of MDSC and Treg immunosuppressive phenotype. Our data suggest that an improved multivalent DC vaccine based on shared tumor antigens induces potent anti-tumor effects and could be combined with checkpoint inhibitors or targeting immunosuppressive cells to further improve their therapeutic efficiency.

The clinical study on treatment of CD19‐directed chimeric antigen receptor‐modified T cells in a case of refractory Richter syndrome

“…So, blockage of immunosuppressive function of TME may enhance effecacy of CART‐19 cells. Certain studies support our hypothesis, anti‐PD‐L1 could augment the antitumor activity of tumor‐directed immunocytes in inhibiting tumor growth . Schuster et al reported a refractory DLBCL patient of primary mediastinal origin with extra‐nodal involvement of small intestine.…”

Identification of Two Subsets of Murine DC1 Dendritic Cells That Differ by Surface Phenotype, Gene Expression, and Function

“…DC1 cells in the skin draining lymph nodes, tumors, and intestines express high levels of CD103 whereas DC1 cells in the spleen have low or undetectable levels (24)(25)(26)(27)(28). The CD8 + subset of DCs has been reported to be more potent than the CD8subset in crosspresenting cell associated protein antigens to conventional CD8 + T cells, and selective depletion of the CD8+ subset markedly attenuates CD8+ T cell immunity to tumors and viruses by virtue of cross antigen presentation (29)(30)(31)(32). CD8 + DCs take up proteins from exogenous cell sources that are the source of the antigens, such as tumor cells and viral infected cells, process the proteins such that the derived peptides are crosspresented to CD8 + T cells after association with MHC receptors on the cell surface (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Acquisition of resistance to vemurafenib leads to interleukin‐10 production through an aberrant activation of Akt in a melanoma cell line

“…Therefore, these results imply that IL‐10 released from melanoma cells suppresses the tumor‐infiltrating DC . Several animal models showed that DC vaccine enhanced the effect of immune checkpoint inhibitors . Therefore, we think DC may play important roles in the antitumor effect of immune checkpoint inhibitors, and dysfunction of the tumor‐infiltrating DC may attenuate the effect of it.…”

“…17 Several animal models showed that DC vaccine enhanced the effect of immune checkpoint inhibitors. 18 Therefore, we think DC may play important roles in the antitumor effect of immune checkpoint inhibitors, and dysfunction of the tumor-infiltrating DC may attenuate the effect of it. Taken together, our results indicate that the acquisition of resistance to BRAF inhibitors is unfavorable for immune checkpoint inhibitors if the patients plan to receive them after receiving BRAF inhibitors.…”