Nanoparticle-based delivery system has been attempted for a couple of decades for cancer immunotherapy (CIT) to modulate immune responses and reduce off-target side effect. For the successful CIT, the extent of antigen presentation by dendritic cell (DC) that phagocytizes tumor associated antigen (TAA) in tumor site and migrates to tumor draining lymph node (TDLN) for an activation of T-cells. For this, recent studies have been trying to make tumor tissue releases TAAs directly, increasing the chance for antigen presenting cells (APCs) to encounter the neoantigens. Photodynamic therapy (PDT), a conventional cancer therapeutic manner that generates reactive oxygen species (ROS) from adjacent oxygen by photosensitizer (PS) under irradiation of light, could induce release of damage-associated molecular patterns (DAMPs) and promote activities of immune cells, along with release of TAAs. Furthermore, PDT mediated generation of ROS is well known as neutrophil chemotaxis, potentiating capability for DC recruitment via granule enzymatic processing the prochemerin into chemerin. Taken together, a PDT can induce both tumor cell death and recruiting DCs, followed by uptake of the as-generated cell debris by APCs which increases the antigen presentation process and further activation of antitumor immune responses. Herein, to introduce PDT-induced immunologic alterations into CIT, we devised the nanoparticle-based delivery system that fulfills a few key requirements: 1) internalized efficiently by the cells at the target site, while the cargo is protected from degradation and scavenging by macrophages during circulation; 2) induces the release of tumor proteins and deliver adjuvant to activate APCs for prolonged immune reaction. In this study, we have developed a MSN-based hypoxia-responsive PS/adjuvant nanocomplex, denoted as CAGE, to enable photodynamic therapy assisted CIT. The surface of chlorin e6 (Ce6)-doped mesoporous silica nanoparticle was decorated with glycol chitosan (GC) and PEG via azobenzene linker, a hypoxia-responsive labile linker. CpG, a short oligonucleotide immunomodulator known to activate the DCs, was loaded onto the surface of CAGE by electrostatic interaction with GC. It was designed that azobenzene linker could be cleaved under intrinsic tumor hypoxia as well as abrupt consumption of local oxygen induced by photodynamic effect, leading to both a detachment of PEG for the tumor specific retention of MSNs and release of CpG/GC complexes. Due to the photodynamic effect of PS and delivery of CpG, the population of tumor infiltrating DCs and its maturation ratio were significantly elevated. An improved activity of DCs, combined with generation of tumor debris by photodynamic effect, was synergistically resulted in increase of antigen presentation of DCs, exhibiting remarkable inhibition of tumor growth in vivo.

Citation Format: Sooseok Im, Won Jong Kim. Multifunctional immunomodulator capable of hypoxia-sensitive adjuvant delivery and photodynamical assistance for DC antigen presentation for cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B017.