Peptide vaccine-conjugated mesoporous carriers synergize with immunogenic cell death and PD-L1 blockade for amplified immunotherapy of metastatic spinal

Abstract

The clinical treatment of metastatic spinal tumor remains a huge challenge owing to the intrinsic limitations of the existing methods. Programmed cell death protein 1 (PD1)/programmed cell death ligand 1 (PD-L1) pathway blockade has been explored as a promising immunotherapeutic strategy; however, their inhibition has a low response rate, leading to the minimal cytotoxic T cell infiltration. To ameliorate the immunosuppressive microenvironment of intractable tumor and further boost the efficacy of immunotherapy, we report an all-round mesoporous nanocarrier composed of an upconverting nanoparticle core and a large-pore mesoporous silica shell (UCMS) that is simultaneously loaded with photosensitizer molecules, the IDO-derived peptide vaccine AL-9, and PD-L1 inhibitor. The IDO-derived peptide can be recognized by the dendritic cells and presented to CD8+ cytotoxic T cells, thereby enhancing the immune response and promoting the killing of the IDO-expressed tumor cells. Meanwhile, the near-infrared (NIR) activated photodynamic therapy (PDT) could induce immunogenic cell death (ICD), which promotes the effector T-cell infiltration. By combining the PDT-elicited ICD, peptide vaccine and immune checkpoint blockade, the designed UCMS@Pep-aPDL1 successfully potentiated local and systemic antitumor immunity and reduced the progression of metastatic foci, demonstrating a synergistic strategy for cancer immunotherapy.

High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma

“…Previous studies have shown that, at the molecular level, the immunological silhouette of these cells death pathways is defined by a set of molecules called damage-associated molecular patterns, including calreticulin (CRT), high-mobility group box-1 (HMGB1) protein, and adenosine triphosphate (ATP) [ 29 ]. CRT is a unique biomarker exposed on the surface of cells undergoing ICD [ 28 , 30 , 31 ]. Furthermore, under normal conditions, CRT is mainly located in the endoplasmic reticulum and is transported to the cell surface in the event of endoplasmic reticulum stress, where it serves as an indicator of ICD [ 28 , 31 ].…”

“…CRT is a unique biomarker exposed on the surface of cells undergoing ICD [ 28 , 30 , 31 ]. Furthermore, under normal conditions, CRT is mainly located in the endoplasmic reticulum and is transported to the cell surface in the event of endoplasmic reticulum stress, where it serves as an indicator of ICD [ 28 , 31 ]. Once exposed on the cell surface, CRT acts as an “eat me” signal, stimulating immature dendritic cells (DCs) and macrophages to engulf dying tumor cells and their apoptotic fragments [ 28 , 31 ].…”

“…Furthermore, under normal conditions, CRT is mainly located in the endoplasmic reticulum and is transported to the cell surface in the event of endoplasmic reticulum stress, where it serves as an indicator of ICD [ 28 , 31 ]. Once exposed on the cell surface, CRT acts as an “eat me” signal, stimulating immature dendritic cells (DCs) and macrophages to engulf dying tumor cells and their apoptotic fragments [ 28 , 31 ]. When secreted into the intercellular stroma, HMGB1 and ATP act as “find me” signals that are rapidly recognized by phagocytic cells [ 29 ].…”

Nanomaterials: small particles show huge possibilities for cancer immunotherapy

“…Although an increasing number of immunotherapy regimens represented by PD-1/PD-L1 inhibitors are being incorporated into the treatment of advanced and metastatic tumors, their clinical effectiveness remains limited due to a firm TIME. To improve this therapeutic dilemma, Dong et al [ 206 ] constructed an immune response-based all-encompassing multi-targeted mesoporous nanoformulation UCMS@Pep-αPDL1. The brief preparation process was that hexagonal UCNPs (upconversion nanoparticles) with a diameter of about 40 nm were coated with dense SiO 2 and macroporous mesoporous silicon on the surface to obtain UCMS, and finally loaded with photosensitizer RB (Rose Bengal), IDO-derived peptide vaccine AL-9, and PD-L1 inhibitor (Fig.…”

Nanotechnology-enabled immunoengineering approaches to advance therapeutic applications

“…While mAb-based checkpoint blockade therapy has tremendous clinical success, systemic administration can still suffer lower efficacy due to premature degradation of the antibody and off-target toxicities. Several groups have worked on the direct delivery of PD-1 antibodies using biodegradable nanocarriers like PLGA [ 9 , 10 ] or large pore mesoporous silica-upconversion nanoparticles (UCNP) [ 11 ]. PD-1 antibodies can be co-delivered with other adjuvants or small molecule inhibitors to improve efficacy.…”