Assistant Professor University of Illinois at Urbana Champaign Urbana, Illinois, United States
Introduction: The ability to modulate the function of antigen presenting cells (e.g., dendritic cells (DCs)) and orchestrate the priming of antigen-specific T cells holds promise to improve the overall cytotoxic T lymphocyte (CTL) response and therapeutic efficacy, and has been actively pursued in therapeutic cancer vaccines. Indeed, Sipuleucel-T, one type of DC vaccines for treating prostate cancer, was among the first FDA-approved cancer immunotherapies. While various other types of cancer vaccines have been actively pursued, Sipuleucel-T remains the only FDA-approved therapeutic vaccine despite a modest therapeutic benefit (4.1-month increase in median survival). Strategies to improve the antitumor efficacy of cancer vaccines, especially DC vaccines, while maintaining the benign safety profile are greatly demanded. DC vaccines function by isolating DCs from the patient’s blood, expanding them in the presence of tumor antigens and adjuvants, and infusing back to patients. Extensive efforts have been made to optimize the source of DCs and antigens, the protocol for expanding antigen-presenting DCs ex vivo, and the administration routes of DCs. However, issues including suboptimal activation of DCs and lack of control over DC function after adoptive transfer remain largely unsolved. The potential dysfunction of adoptively transferred DCs during the blood circulation and tissue penetration, as a result of the shearing force, metabolic stress, and apoptotic signals, often undermines the resultant CTL response and therapeutic benefit, but strategies for in vivo targeted modulation of adoptively transferred DCs are lacking.
Materials and
Methods: Here we introduce a metabolic labeling and targeting technology that enables targeted modulation of adoptively transferred DCs in vivo (Fig. 1a). We previously reported that DCs can be metabolically labeled with chemical tags (e.g., azido groups) via the metabolic glycoengineering process of unnatural sugars. In this study, we carefully examined the impact of metabolic glycan labeling on the membrane property and activation status of DCs, and for the first time, apply the metabolic glycan labeling and targeting technology to the context of DC vaccine.
Results, Conclusions, and Discussions: We found that the metabolic glycan labeling process itself is able to reduce the mobility of proteins on DC membrane and upregulate the activation markers of DCs (Fig. 1b), leading to the improved ability of DCs to process and present peptide and protein antigens and subsequently prime antigen-specific CD8+ T cells. By simply adding azido-sugars to the culture medium of DCs during the expansion of antigen-presenting DCs, an essential step for clinical manufacturing of DC vaccines, the CTL response and antitumor efficacy of DC vaccines are significantly improved. We further demonstrated that azido groups on the surface of DCs, introduced via metabolic glycan labeling, can mediate conjugation of dibenzocyclooctyne (DBCO)-modified agents (e.g., IL-15 and IL-2) via efficient and bioorthogonal click chemistry (Fig. 1a). The surface conjugation of IL-15 onto adoptively transferred, antigen-presenting DCs dramatically improves the T cell priming process, and further enhances the antigen-specific CD8+ T cell response and antitumor efficacy. This metabolic labeling and targeting technology provides a generalizable approach to modulating DCs for the development of enhanced DC vaccines, with minimal interference upon the clinical manufacturing process.
