Abstract
BackgroundImmunotherapeutic strategies to stimulate anti-tumor immunity are promising approaches for cancer treatment. A major barrier to their success is the immunosuppressive microenvironment of tumors, which inhibits the functions of endogenous dendritic cells (DCs) that are necessary for the generation of anti-tumor CD8+ T cells. To overcome this problem, autologous DCs are generated ex vivo, loaded with tumor antigens, and activated in this non-suppressive environment before administration to patients. However, DC-based vaccines rarely induce tumor regression.Methodology/Principal FindingsWe examined the fate and function of these DCs following their injection using murine models, in order to better understand their interaction with the host immune system. Contrary to previous assumptions, we show that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells.Conclusions/SignificanceThis reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches should focus on creating DC vaccines that are more effective at directly priming T cells, or abrogating the tumor induced suppression of endogenous DCs.
Highlights
Therapeutic vaccines are a considered a realistic approach for cancer immunotherapy, because animal studies have shown that recognition of tumor associated antigens (TAAs) by cytotoxic T lymphocytes can lead to the destruction of tumor cells [1,2,3]
CD8+ T cell priming by peptide loaded dendritic cells (DCs) vaccine requires endogenous antigen presenting cells
While the T cell response to LmOVA should depend on antigen presentation by the endogenous bone-marrow-derived hematopoietic cells [22], the priming by peptide-DCs in these mice could be a result of either direct interaction of the injected DCs with endogenous T cells, or antigens from the injected DCs captured by host cells and subsequently presented to T cells
Summary
Therapeutic vaccines are a considered a realistic approach for cancer immunotherapy, because animal studies have shown that recognition of tumor associated antigens (TAAs) by cytotoxic T lymphocytes can lead to the destruction of tumor cells [1,2,3]. In order to generate tumor-specific T cells with full effector function they first must undergo priming by dendritic cells (DCs), the antigen presenting cell (APC) most efficient at initiating potent CD8+ T-cell responses [4,5]. Understanding how to modulate DC functions may be essential to therapeutically inducing anti-tumor immune responses [6,7]. A major barrier to their success is the immunosuppressive microenvironment of tumors, which inhibits the functions of endogenous dendritic cells (DCs) that are necessary for the generation of anti-tumor CD8+ T cells. To overcome this problem, autologous DCs are generated ex vivo, loaded with tumor antigens, and activated in this non-suppressive environment before administration to patients.
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