Mnox Nanoenzyme Armed CAR-NK Cells Enhance Solid Tumor Immunotherapy by Alleviating the Immunosuppressive Microenvironment.

Adoptively transferred cells usually suffer from exhaustion, limited expansion, and poor infiltration, partially attributing to the complicated immunosuppressive microenvironment of solid tumors. Therefore, it is necessary to explore more effective strategies to improve the poor tumor microenvironment (TME) to efficaciously deliver and support extrinsic effector cells in vivo. Herein, an intelligent biodegradable hollow manganese dioxide nanoparticle (MnOX) that possesses peroxidase activity to catalyze excess H2O2 in the TME to produce oxygen and relieve the hypoxia of solid tumors is developed. MnOX nanoenzymes modified with CD56 antibody could specifically bind CAR-NK (chimeric antigen receptor modified natural killer) cells. It is demonstrated that CAR-NK cells incorporated with MnOX nanoenzymes effectively infiltrate into tumor tissues with an improved TME, which results in superior antitumor activity in solid tumor-bearing mice. The antibody connection between MnOX nanoenzymes and CAR-NK endows the lowest efficient dosage of MnOX. This study features a smart synergistic immunotherapy approach for solid tumors using MnOX nanoenzyme-armed CAR-NK cells, which would provide a valuable tool for immunocyte therapy in solid tumors.

p120-catenin promotes innate antiviral immunity through stabilizing TBK1-IRF3 complex.

TBK1-IRF3 complex plays vital roles in antiviral immune responses, its regulatory mechanisms are currently incompletely understood. p120-catenin (p120), an armadillo-repeat protein, mainly regulates the stability of classical cadherins and the development of epithelial-to-mesenchymal transitions (EMTs). Here we report that p120 is a positive regulator of type I IFN production. Ectopic expression of p120 enhanced Vesicular stomatitis virus and Sendai-virus-induced type I IFN production, whereas knockdown of p120 expression suppressed type I IFN production. Mechanistically, p120 promoted phosphorylation of IRF3 via stabilizing the TBK1-IRF3 complex. Consistently, p120 knock down mice are more susceptible to VSV infection as indicated by higher tissue viral titers, less IFN-I production and greater infiltration of immune cells. This study reveals p120 as an important positive regulator in innate immunity and identifies that p120 facilitates host antiviral response through stabilizing TBK1-IRF3 complex.

Switch receptor T3/28 improves long-term persistence and antitumor efficacy of CAR-T cells.

BACKGROUND: Chimeric antigen receptor (CAR) T cells have been successfully used in tumor immunotherapy due to their strong antitumor responses, especially in hematological malignancies such as B cell acute lymphoid leukemia. However, on-target off-tumor toxicity and poor persistence severely limit the clinical application of CAR-T cell therapy. METHODS: T-cell immunoglobulin mucin domain molecule 3 (TIM-3) was used to develop a second-generation 41BB CD19 CAR linked with a T3/28 chimera, in which truncated extracellular TIM-3 was fused with the CD28 transmembrane and cytoplasmic domains. The efficacy of T3/28 CAR-T cells was evaluated in vitro and in vivo. RESULTS: We demonstrated that the switch receptor T3/28 preserved the TCM phenotype, improved proliferative capacity, and reduced exhaustion of CAR-T cells, resulting in superior in vitro and in vivo antitumor activity in B lymphoma. Importantly, the switch receptor T3/28 substantially prolonged the persistence of CAR-T cells, and the interleukin-21/Stat3 axis probably contributed to the enhanced cytotoxicity of T3/28 CAR-T cells. CONCLUSION: Overall, the T3/28 chimera significantly prolonged the persistence of CAR-T cells, and T3/28 CAR-T cells possessed potent antitumor activity in mice, shedding new light on potential improvements in adoptive T cell therapies.

Surface specifically modified NK-92 cells with CD56 antibody conjugated superparamagnetic Fe3O4 nanoparticles for magnetic targeting immunotherapy of solid tumors.

Although there has been significant progress in the development of tumor immunotherapies, many challenges still exist for the treatment of solid tumors. Natural killer (NK) cells possess broad-spectrum cytotoxicity against tumors, but their limited migration and infiltration abilities restrict their application in solid tumor therapies. Here, we combined a facile and efficient magnetic-targeting strategy with NK cell-based therapy to develop a novel immunotherapy approach for treating solid tumors. Anti-CD56 antibodies were conjugated with Fe3O4 nanoparticles, which could specifically bind with NK-92 cells endowing them with a magnetic field driven targeting ability. These NK-Fe3O4 biohybrid nanoparticles were able to facilitate directional migration to the tumor site in vivo under external magnetic field guidance and efficiently inhibit tumor growth. These functionalized NK cells represent a novel approach for solid tumor therapy and may provide a promising modality for cancer interventions in the future.