Photosensitizer and Light Pave the Way for Cytosolic Targeting and Generation of Cytosolic CD8 T Cells Using PLGA Vaccine Particles

Abstract

The generation of CTLs is crucial in the immunological fight against cancer and many infectious diseases. To achieve this, vaccine Ags need to be targeted to the cytosol of dendritic cells, which can activate CD8 T cells via MHC class I (MHCI). Therefore, such targeting has become one of the major objectives of vaccine research. In this study, we aimed to bypass the unwanted and default MHC class II Ag presentation and trigger MHCI presentation by using a photosensitizer that, upon light activation, would facilitate cytosolic targeting of codelivered Ag. Poly(lactide-co-glycolide) microparticles ∼1 μm size were loaded with OVA and the photosensitizer tetraphenyl chlorine disulphonate (TPCS2a) and administered intradermally in mice, which were illuminated 1 d later for activation of the photosensitizer. Immunization in the presence of TPCS2a significantly increased activation of CD8 T cells compared with immunization without TPCS2a and as measured by CD8 T cell proliferation, production of proinflammatory IFN-γ, TNF-α, and IL-2, and prevention of tumor growth. Cytotoxicity was demonstrated by granzyme B production in vitro and by in vivo killing of CFSE-labeled targets. CD4-dependent Ab responses were abrogated in mice immunized with TPCS2a-containing particles, suggesting that photosensitization facilitated a shift from default MHC class II toward MHCI Ag presentation. Hence, vaccine particles with Ag and photosensitizers proved an effective vehicle or adjuvant for stimulation of CTLs, and they may find potential application in therapeutic cancer vaccination and in prophylactic and therapeutic vaccination against intracellular infections.

Photochemical Internalization of Peptide Antigens Provides a Novel Strategy to Realize Therapeutic Cancer Vaccination

“…Our results clearly showed that PCI technology could effectively induce and significantly enhance antigen-specific CD8+ CTL responses to both peptide antigens. In earlier studies, a similar effect has been demonstrated with the ovalbumin protein antigen in mice adoptively transferred with OVA 257–264 -specific transgenic T cells ( 21 – 23 , 50 , 51 ). However, the results in the present work are the first demonstration of priming of CD8+ T cells from the endogenous T cell pool with clinically relevant peptide sequences, moving the technology substantially closer to a clinical use for peptide vaccination in humans.…”

Photochemical Internalization: Light Paves Way for New Cancer Chemotherapies and Vaccines

“…As some tumor cells, e.g., ovarian cancer or lung adenocarcinoma, express folate receptors on their surface, folic acid was applied to facilitate delivery of chemotherapeutic agents [17] in patients with platinum-refractory epithelial ovarian, primary peritoneal, or endometrial cancer [18] and progressive lung adenocarcinoma [19]. Other pharmaceutical strategies for cytosolic targeting of drugs include cationic particles to shuffle antigens across the negatively charged cellular membrane [20,21], pH-sensitive and fusogenic liposomes that break up acidified phagolysosomes [22,23], and micelle-based immune-stimulating complexes (ISCOMs) that may facilitate antigen cross-presentation [22,24]. Very recently, reports on the use of photochemical internalization (PCI), which is a further development of PDT, has been suggested as a method to internalize cytotoxic therapeutics in tumor cells [25][26][27][28][29][30][31][32] or vaccine antigens in antigen-presenting cells (APC) [20,22,[33][34][35][36][37].…”

“…Bruno et al demonstrated that PCI-based vaccination could be performed with antigen and photosensitizer contained in a particulate antigen delivery system composed of poly(lactide-co-glycolide) (PLGA) microparticles of approximately 1 µm in size [22]. Mice immunized with particles containing OVA and TPCS2a showed stronger CD8 T-cell proliferation than mice immunized with PLGA particles containing OVA antigen without TPCS2a.…”

“…Successful stimulation of tumor-specific immunity by PCI has been demonstrated in several mouse models of cancer. PCI mediated induction of antigen-specific CD8 T-cell proliferation and IFN-γ production [20,22,[33][34][35][36], prevention of tumor grafting [34,35], suppression of tumor growth, and improved progression-free survival in mice [35,37]. Studies have demonstrated the mechanism of antigen and photosensitizer uptake in APCs and that, upon application of light, the antigen is released from endosomes or even phagolysosomes into the cytosol [34][35][36].…”

Delivery of therapeutics with nanoparticles: what's new in cancer immunotherapy?

“…In order to promote an immune response resulting in the priming of cytotoxic T‐lymphocytes, antigens need to be delivered in the cytoplasm of dendritic cells, thereby Bruno et al developed PLGA microparticles loaded with OVA and functionalized with tetraphenyl chlorine disulphonate as a photosensitizer to trigger the release of the antigen in the cytosolic compartment. The immunization with these particles induced the production of CD8 T‐lymphocytes and the prevention of tumor growth …”