Abstract
Critical to the generation of an effective therapeutic antitumor immune response is the elicitation of effective antigen presentation coupled with overcoming tumor-immune escape mechanisms. Towards this end, we aimed to understand the therapeutic effectiveness of a polymer based vaccine approach at enhancing the anti-tumor responses in a tumor-bearing mouse model. While we and others have previously demonstrated the effectiveness of PLGA based systems in delivering antigen etc., studies scarcely focus on understanding the immunological mechanisms of polymer based therapies in tumor bearing treatment models. Considering tumors modulate the immune system and consequently the efficacy of therapies, understanding treatment mechanisms in the presence of tumor will help lead to more efficacious treatment options. We demonstrate here that a poly(lactic-co-glycolic acid) (PLGA) based delivery system encapsulating tumor antigen (OVA) and the TLR9 agonist CpG motif DNA administered into the tumor microenvironment initiates an effective type 1 mediated (IFN-γ producing) anti-tumor response in a syngeneic murine model of T cell lymphoma (E.G7-OVA). Although E.G7-OVA tumors spontaneously generate antigen specific CTLs in draining lymph nodes (LN), tumors progress rapidly. Modulation of the tumor microenvironment via local PLGA based therapy led to the generation of a systemic antigen specific Th1 response, absent in the non-polymer delivery method, subsequently associated with reduced tumor growth and prolongation of survival. These studies provide further insight into the use of a PLGA-based therapeutic approach at modulating the tumor microenvironment and highlight the need for analyzing the treatment effects in a tumor bearing model.
Highlights
Studies from our and other laboratories clearly demonstrate that the tumor microenvironment represents a complex interface between the immune system and the tumor, leading to poor antigen presentation, elevated levels of IL-10 or increased Treg activity [1,2,3,4,5]
We demonstrate here that a poly(lactic-co-glycolic acid) (PLGA) based delivery system encapsulating tumor antigen (OVA) and the TLR9 agonist CpG motif DNA administered into the tumor microenvironment initiates an effective type 1 mediated (IFN-γ producing) anti-tumor response in a syngeneic murine model of T cell lymphoma (E.G7-OVA)
The studies presented here demonstrate the ability of a polymer delivery system to induce a Th1 producing tumor antigen specific anti-tumor immune response in a tumor bearing mouse model
Summary
Studies from our and other laboratories clearly demonstrate that the tumor microenvironment represents a complex interface between the immune system and the tumor, leading to poor antigen presentation, elevated levels of IL-10 or increased Treg activity [1,2,3,4,5]. Studies presented in this report build on our prior demonstration that polymer encapsulating CpG motif oligonucleotides effectively activates antigen-presenting dendritic cell populations in vitro [13]. In this prior work we have demonstrated enhanced expression of CD80, CD86, MHCII and secretion of IL-12 associated with the stimulation of Th1 T cell responses.
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