Converting Immune Cold into Hot by Biosynthetic Functional Vesicles to Boost Systematic Antitumor Immunity

Abstract

Summary Immune cold tumor characterized by low immunogenicity, insufficient and exhausted tumor-infiltrating lymphocytes, and immunosuppressive microenvironment is the main bottleneck responsible for low patient response rate of immune checkpoint blockade. Here, we developed biosynthetic functional vesicles (BFVs) to convert immune cold into hot through overcoming hypoxia, inducing immunogenic cell death, and immune checkpoint inhibition. The BFVs present PD1 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the surface, whereas load catalase into their inner core. The TRAIL can specifically induce immunogenic death of cancer cells to initiate immune response, which is further synergistically strengthened by blocking PD1/PDL1 checkpoint signal through ectogenic PD1 proteins on BFVs. The catalase can produce O 2 to overcome tumor hypoxia, in turn to increase infiltration of effector T cells while deplete immunosuppressive cells in tumor. The BFVs elicit robust and systematic antitumor immunity, as demonstrated by significant regression of tumor growth, prevention of abscopal tumors, and excellent inhibition of lung metastasis.

Reversing cold tumors to hot: An immunoadjuvant-functionalized metal-organic framework for multimodal imaging-guided synergistic photo-immunotherapy

“…Radiotherapy and chemotherapy, conventional first-line treatments, are troubled by tumor recurrence and metastasis, because of the side effect and the serious injury of host's immunity [ 3 ]. Recently, immunotherapy for cancer treatment has emerged as a promising therapeutic modality for recurrent or metastasized cancer, as it converts cold tumors into hot tumors [ [4] , [5] , [6] , [7] ]. Immunotherapy aims to induce or expand the host's anticancer immune response, which can distinguish the subtle differences between cancerous cells and healthy cells.…”

Protocol to prepare functional cellular nanovesicles with PD1 and TRAIL to boost antitumor response

“…All of the above corresponding results can be found in our recent iScience publication ( Wu et al., 2020 ).…”

“…FCNVs ultrastructure, integrity and morphology are evaluated by transmission electron microscopy (TEM). For detailed instructions on how to perform FCNVs characterization and the corresponding results can be found in our recent iScience publication ( Wu et al., 2020 ).…”

“…We demonstrated the ability of this protocol to prepare FCNVs with high purity, which is a prerequisite to obtain reliable data for antitumor immune responses. For full details, we refer to ( Wu et al., 2020 ). Theoretically, in addition to PD1 and TRAIL, other functional proteins decorated cellular nanovesicles can be also obtained by our protocols.…”

“…TRAIL specifically induces immunogenic cancer cell death to initiate an immune response, and ectogenic PD1 blocks the PD1/PDL1 checkpoint signal to reactivate anergic tumor-specific CD8+ T cells. For complete details on the use and execution of this protocol, please refer to Wu et al. (2020) .…”