Abstract
BackgroundDeveloping safe and effective cancer vaccine formulations is a primary focus in the field of cancer immunotherapy. Dendritic cells (DC) are currently employed as cellular vaccine in clinical trials of tumor immunotherapy. Recognizing the critical role of DCs in initiating anti-tumor immunity has resulted in the development of several strategies that target vaccine antigens to DCs to trigger anti-tumor T cell responses. To increase the efficiency of antigen delivery systems for anti-tumor vaccines, encapsulation of tumor-associated antigens in polymer nanoparticles (NPs) has been established.MethodsIn this study, the effect of tumor lysate antigen obtained from three stage III breast cancer tissues encapsulated within PLGA NPs to enhance the DC maturation was investigated. The T-cell immune response activation was then fallowed up. Fresh breast tumors were initially used to generate tumor lysate antigens containing poly lactic-co-glycolic acid (PLGA) NP. The encapsulation efficiency and release kinetics were profiled. The efficiency of encapsulation was measured using Bradford protein assays measuring the dissolved NPs. The stability of released antigen from NPs was verified using SDS-PAGE. To evaluate the hypothesis that NPs enhances antigen presentation, including soluble tumor lysate, tumor lysate containing NPs and control NPs the efficiency of NP-mediated tumor lysate delivery to DCs was evaluated by assessing CD3+ T-cell stimulation after T cell/and DCs co-culture.ResultsThe rate of encapsulation was increased by enhancing the antigen concentration of tumor lysate. However, increasing the antigen concentration diminished the encapsulation efficiency. In addition, higher initial protein contenting NPs led to a greater cumulative release. All three patients released variable amounts of IFN-γ, IL-10, IL-12 and IL-4 in response to re-stimulation. T cells stimulated with lysate-pulsed DCs induced a substantial increase in IFN-γ and IL-12 production. We demonstrated that NPs containing tumor lysate can induce maturation and activation of DCs, as antigen alone does.ConclusionPLGA-NPs are attractive vehicles for protein antigen delivery which effectively induce stimulation and maturation of DCs, allowing not only an enhanced antigen processing and immunogenicity or improved antigen stability, but also the targeted delivery and slow release of antigens.
Highlights
Developing safe and effective cancer vaccine formulations is a primary focus in the field of cancer immunotherapy
The data of this study showed that the tumor lysate loaded NPs triggers a more efficient maturation of monocyte-derived Dendritic cells (DC) compared to either tumor lysate or NPs alone (P ≤ 0.05) (Figs. 5 and 6)
In comparison to tumor lysate alone, tumor antigen loaded NP pulsed DCs substantially released more IL-12 and IL-10 cytokines, our findings revealed that the level of secreted IL-12 was higher than of IL-10 significantly (P ≤ 0.05) (Fig. 8a, b)
Summary
Developing safe and effective cancer vaccine formulations is a primary focus in the field of cancer immunotherapy. Cell-mediated immune mechanisms have been determined in breast cancers [4] These immune responses are induced by breast tumor cells and lead to a systemic anti-tumor immunity and regression of breast cancer [5, 6]. Immunotherapy may be effective in treating patients with breast cancer This kind of therapy concentrates on the induction and enhancement of immune responses against tumors. In a limited number of malignancies in which tumor-associated antigens have been determined, antitumor vaccine strategies have proven to be partially effective, predominantly based on the loading of professional antigen-presenting cells (APCs), including DCs [7]. Using DCs which are the most potent APCs with the unique capability to induce primary immune responses against tumor-associated antigens in cancer treatment is a promising approach [10, 11]. Both large “micro-” and small “nano-” particles can efficiently be taken up by both cell types [14]
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