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

Zhenqing Wang,Huiren Wang,Annan Hu,Xilei Li,Liang Chen,Wenxing Wang,Jian Dong,Xiaomin Li,Bo Tian,Yiqun Ma

doi:10.1186/s12951-021-00975-5

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.

Highlights

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors of the lung and has the second highest incidence and highest morbidity worldwide [1]
The transmission electron microscopy (TEM) images show the hexagonal morphology of the prepared upconverting nanoparticles (UCNPs) with an average diameter of approximately 40 nm (Fig. 2A)
UCMS@Pep-aPDL1-Rose Bengal (RB) combined with photodynamic therapy (PDT) was shown to have the best therapeutic efficacy against tumor progression, followed by UCMS@Pep-aPDL1 and UCMS@Pep therapy. These results indicate that the integration of AL-9 peptide vaccine with PDT has a synergistic effect in promoting antitumor effect with anti programmed cell death ligand 1 (PD-L1) therapy

Summary

Introduction

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors of the lung and has the second highest incidence and highest morbidity worldwide [1]. Effective treatments can prolong the survival of NSCLC patients, the bone metastasis caused by. Immunotherapy has emerged as a revolutionary technology for cancer treatment owing to the success of immune checkpoint block (ICB) [10]. ICB therapy could potentially reverse an immunosuppressive tumor microenvironment and further induce antitumor immunologic response to eliminate local and disseminated tumors [11]. The systemic administration of monoclonal antibodies may cause “on-target but off-tumor” effects, resulting in adverse immune-related events, such as dermatitis, colitis, and hepatitis [12]. A successful immunotherapy platform should potentiate cytotoxic T cell immune responses by modulating an immunosuppressive microenvironment, and significantly enhance the susceptibility of tumors to immunotherapy with reduced off-target toxicity and immune-related adverse effects [16]

Methods

Results

Conclusion