Genetic Vaccines To Potentiate the Effective CD103+ Dendritic Cell–Mediated Cross-Priming of Antitumor Immunity

Abstract

The development of effective cancer vaccines remains an urgent, but as yet unmet, clinical need. This deficiency is in part due to an incomplete understanding of how to best invoke dendritic cells (DC) that are crucial for the induction of tumor-specific CD8+T cells capable of mediating durable protective immunity. In this regard, elevated expression of the transcription factor X-box-binding protein (XBP1) in DC appears to play a decisive role in promoting the ability of DC to cross-present antigens (Ag) to CD8+T cells in the therapeutic setting. Delivery of DNA vaccines encoding XBP1 and tumor Ag to skin DC resulted in increased IFN-α production by plasmacytoid DC (pDC) from skin/tumor draining lymph nodes (dLN) and the cross-priming of Ag-specific CD8+T cell responses associated with therapeutic benefit. Anti-tumor protection was dependent on cross-presenting Batf3+DC, pDC and CD8+T cells. CD103+DC from the skin/tumor dLN of the immunized mice appeared responsible for activation of Ag-specific naïve CD8+T cells, but were dependent on pDC for optimal effectiveness. Similarly, human XBP1 improved the capacity of human blood- and skin-derived DC to activate human T cells. These data support an important intrinsic role for XBP1 in DC for effective cross-priming and orchestration of Batf3+DC–pDC interactions, thereby enabling effective vaccine induction of protective anti-tumor immunity.

Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival

“…Despite the presence of XBP1 levels at basal stage, a typical XBP1s gene signature could not be observed in DCs ( 19 and data not shown). Rather, IRE1/XBP1s might trigger as yet poorly understood cell type specific gene programs 63–65 that in DCs could be linked to their antigen presentation capacity 66 , type I IFN production 67,68 or overall survival (this study).…”

Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth

“…Braf V600E /Pten-driven melanoma was generated by inducing oncogene Braf V600E expression with 4-hydroxytamoxifen (4-HT; Sigma) in B6-Tyr: Cre (ER)T2 Braf CA Pten lox/lox mice with correct genotype (presence of Tyr:Cre (ER)T2 , Braf CA and homozygous Pten lox/lox ; ref. 22). Mice (7-to 8-week-old) were housed in a pathogen-free facility under controlled temperature, humidity, and 12-hour light/dark cycle with a commercial rodent diet and water available ad libitum.…”

“…These results were confirmed with an inducible melanoma model. Nerve transection in BP mice was performed 1 week after melanoma induction with topical 4-HT, as described previously (22,25), and following minocycline injections (Fig. 6D).…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…[2][3][4][48][49][50][51] On the other side, malignant cells succumbing to a putative ICD inducer can be fed to dendritic cells (DCs), 2,44,52-55 followed by (1) phagocytosis assays [56][57][58][59][60][61][62] ; (2) assessment of activation markers on the DC surface (e.g., CD80, CD86, MHC Class II) and functional markers in conditioned media (e.g., interleukin-6 or IL6, IL1b, IL12p70) 54,[63][64][65][66][67][68][69][70][71][72] priming assays with syngeneic lymphocytes. [73][74][75][76][77][78][79][80][81] Although none of these assays (alone or in combination) can reliably predict the ability of a specific intervention to cause ICD, the use of surrogate approaches is highly convenient for screening purposes or when studies are focused on the human model. 2,3,44,48,82 A number of mechanisms regulate the capacity of a particular agent to drive bona fide ICD and the ability of the host to perceive such an instance of cell death as immunogenic, and hence respond with potentially curative TAA-specific adaptive immunity.…”