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Programmable Bispecific Nano-immunoengager That Captures T Cells and Reprograms Tumor Microenvironment.

ABSTRACT: Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective infiltration of T effector (T_eff) cells to tumors and the immunosuppressive tumor microenvironment (TME). Here, we report a programmable tumor cells/T_eff cells bispecific nano-immunoengager (NIE) that can circumvent these limitations to improve ICB therapy. The peptidic nanoparticles (NIE-NPs) bind tumor cell surface α₃β₁ integrin and undergo in situ transformation into nanofibrillar network nanofibers (NIE-NFs). The prolonged retained nanofibrillar network at the TME captures T_eff cells via the activatable α₄β₁ integrin ligand and allows sustained release of resiquimod for immunomodulation. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.

SUBMITTER: Zhang L

PROVIDER: S-EPMC9479133 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Programmable Bispecific Nano-immunoengager That Captures T Cells and Reprograms Tumor Microenvironment.

Zhang Lu L Bo Ruonan R Wu Yi Y Li Longmeng L Zhu Zheng Z Ma Ai-Hong AH Xiao Wenwu W Huang Yanyu Y Rojalin Tatu T Yin Xingbin X Mao Chunping C Wang Fengyi F Wang Yongheng Y Zhang Hongyong H Low Kelmen E KE Lee Kiana K Ajena Yousif Y Jing Di D Zhang Dalin D Baehr Christopher M CM Liu Ruiwu R Wang Lei L Li Yuanpei Y Lam Kit S KS

Nano letters 20220804 17

Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective infiltration of T effector (Teff) cells to tumors and the immunosuppressive tumor microenvironment (TME). Here, we report a programmable tumor cells/Teff cells bispecific nano-immunoengager (NIE) that can circumvent these limitations to improve ICB therapy. The peptidic nanoparticles (NIE-NPs) bind tumor cell surface α3 ...[more]

PMID: 35926215

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Project description:BackgroundLung cancer is the leading cause of cancer-related death worldwide. We previously found that Mediator complex subunit 23 (MED23) is important for the tumourigenicity of lung cancer cells with hyperactive Ras activity in vitro, although the in vivo function of MED23 in lung tumourigenesis remains to be explored.MethodsIn this study, we utilized well-characterized KrasG12D-driven non-small cell lung cancer mouse model to investigate the role of MED23 in lung cancer. The lung tumour progression was evaluated by H&E and IHC analysis. Western blotting and qRT-PCR assays were performed to detect changes in gene expression. Immune cells were analyzed by FACS technology. RNA-seq and reporter assays were conducted to explore the mechanism.ResultsWe observed that lung epithelial Med23 deletion by adeno-Cre resulted in a significant increase in KrasG12D tumour number and size, which was further verified with another mouse model with Med23 specifically deleted in alveolar type II cells. Mice with lung-specific Med23 deficiency also exhibited accelerated tumourigenesis, and a higher proliferation rate for tumour cells, along with increased ERK phosphorylation. Notably, the numbers of infiltrating CD4+ T cells and CD8+ T cells were significantly reduced in the lungs of Med23-deficient mice, while the numbers of myeloid-derived suppressor cells (MDSCs) and Treg cells were significantly increased, suggesting the enhanced immune escape capability of the Med23-deficient lung tumours. Transcriptomic analysis revealed that the downregulated genes in Med23-deficient lung tumour tissues were associated with the immune response. Specifically, Med23 deficiency may compromise the MHC-I complex formation, partially through down-regulating B2m expression.ConclusionsCollectively, these findings revealed that MED23 may negatively regulate Kras-induced lung tumourigenesis in vivo, which would improve the precise classification of KRAS-mutant lung cancer patients and provide new insights for clinical interventions.

Project description:The MUC1 cytoplasmic tail (MUC1.CT) conducts signals from spatial and extracellular cues (growth factor and cytokine stimulation) to evoke a reprogramming of the cellular transcriptional profile. Specific phosphorylated forms of the MUC1.CT achieve this function by differentially associating with transcription factors and redirecting their transcriptional regulatory capabilities at specific gene regulatory elements. The specificity of interaction between MUC1.CT and several transcription factors is dictated by the phosphorylation pattern of the 18 potential phosphorylation motifs within the MUC1.CT. To better appreciate the scope of differential gene expression triggered by MUC1.CT activation, we performed microarray gene expression analysis and chromatin immunoprecipitation (ChIP)-chip promoter analysis and identified the genome-wide transcriptional targets of MUC1.CT signaling in pancreatic cancer. On a global scale, MUC1.CT preferentially targets genes related to invasion, angiogenesis and metastasis, suggesting that MUC1.CT signaling contributes to establishing a reactive tumor microenvironment during tumor progression to metastatic disease. We examined in detail the molecular mechanisms of MUC1.CT signaling that induces the expression of connective tissue growth factor (CTGF/CCN2), a potent mediator of ECM remodeling and angiogenesis. We demonstrate a robust induction of CTGF synthesis and secretion in response to serum factors that is enabled only when MUC1 is highly expressed. We demonstrate the requirement of phosphorylation at distinct tyrosine motifs within the MUC1.CT for MUC1-induced CTGF expression and demonstrate a phosphorylation-specific localization of MUC1.CT to the CTGF promoter. We found that MUC1 reorganizes transcription factor occupancy of genomic regions upstream of the CTGF gene, directing ?-catenin and mutant p53 to CTGF gene regulatory elements to promote CTGF expression and destabilizing the interaction at these regions of the transcriptional repressor, c-Jun. With this example we illustrate the capacity of MUC1.CT to mediate transcription factor activity in a context-dependent manner to achieve wide spread and robust changes in gene expression and facilitate creation of the reactive tumor microenvironment.

Dataset Information

Programmable Bispecific Nano-immunoengager That Captures T Cells and Reprograms Tumor Microenvironment.

Publications

Programmable Bispecific Nano-immunoengager That Captures T Cells and Reprograms Tumor Microenvironment.

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