Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice

Abstract

Leukemia immunotherapy frequently does not meet expectation, one of the handicaps being tumor exosome (TEX)-promoted immunosuppression. We here asked, using the mouse myeloid leukemia WEHI3B and the renal cell carcinoma line RENCA, whether dendritic cell (DC) vaccination suffices to counterregulate TEX-induced immunosuppression and whether TEX could serve as tumor antigen for DC-loading. DC-vaccination significantly prolonged the survival time of WEHI3B-bearing mice, TEXloaded DC (DC-TEX) being superior to lysate-loaded DC (DC-lys), even an excess of TEX not interfering with immune response induction. The superior response to DC-TEX was accompanied by an increase in WEHI3B-specific CD41 T cells, evaluated by trogocytosis and proliferation. Similar findings accounted for DC loaded with RENCA TEX. TEX was efficiently taken-up by DC and TEX uptake supported CD11c, MHCII and IL12 upregulation in DC. Importantly, TEX was partly recruited into the MHCIIloading compartment such that "TEX" presentation time and recovery in T cells significantly exceeded that of tumor-lysate. Thus, TEX did not drive DC into a suppressive phenotype and were a superior antigen due to higher efficacy of TEXpresentation that is supported by prolonged persistence, preferential processing in the MHCII-loading compartment and pronounced trogocytosis by T helper cells. TEX is present in tumor patients' sera. TEX, recovered and enriched from patients' sera, might well provide an optimized, individual-specific antigen source for DC-loading and vaccination.Cancer therapy can profit from supportive immunotherapy, less burdened by side effects than radio-or chemotherapy.

Exosomes and tumor-mediated immune suppression

“…In the TME, TEX are considered promoters of tumor-mediated immunosuppression. It has been suggested, however, that the immunopotentiating role of TEX could be harnessed for use in vaccination strategies, as TEX carry membrane-associated TAAs and could serve as components of antitumor vaccines (23).…”

Enhancement of Anti-Leukemia Immunity by Leukemia–Derived Exosomes Via Downregulation of TGF-β1 Expression

“…Moreover, we demonstrated that exosomal TGF-β1 could be downregulated through shRNA-mediated gene silencing of parental cells, suggesting the feasibility and conveniences of artificially modulating the protein composition in exosomes via genetic modifications. Previous studies had reported that TEXs were predominantly internalized by DCs and directly influenced the maturation and function of DCs [7, 33]. Yang et al reported that TEX exerted an inhibitory effect on DC maturation and might even potentially predispose DCs towards a tolerogenic phenotype via TGF-β1, indicating that downregulating exosomal TGF-β1 might dramatically reverse the immunosuppressive effect in DCs [13].…”

“…It has been reported that most tumor cells constitutively secret exosomes and furthermore, the exosomes derived from tumor cells (TEXs) are highly enriched in tumor associated antigens (TAA) and in a series of immune-related proteins such as histocompatibility complex (MHC) molecules and heat shock proteins (HSPs) [4, 5]. Accumulated evidence has demonstrated that TEXs could initiate a very potent and specific antitumor immunity with preventive or therapeutic effects [5-7]. In a previous study, we have demonstrated that leukemia cells can release exosomes, which harbor native antigens from their parental cells, thus providing a rationale for the development of leukemia cell-derived exosomes (LEX) as an attractive anti-leukemia vaccine for the targeted eradication of MRLs [6, 8].…”

Therapeutic and diagnostic applications of extracellular vesicles

“…CEA, GP100, HER2, melan-A, PSMA) [32,195] and likely to date unknown tumor antigens. This is not only of interest from a diagnostic point of view but also makes tumor-derived EVs, which have shown to outperform free antigens [193,196] and whole tumor lysate [197,198], an attractive candidate to evaluate as a cell-free vaccine. Building on these promising observations, a clinical trial has been conducted using EVs isolated from ascites fluid.…”