Materials Today Bio
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2023
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IF 8.2
Yuxiang Tang,WeiQi Yao,Hang Hu,Wei Xiong,Heng Mei,Yu Hu
TGF-β is widely existed in tumor microenvironment, taking part in tumorigenesis process including angiogenesis, cancer associated fibroblast (CAF) proliferation, and immunosuppression. It inhibited the activation, proliferation, migration and differentiation of T cells, in which way caused a limited therapeutic effects of chimeric antigen receptor T (CAR-T) towards solid tumor such as lymphoma. To targeted block TGF-β at tumor site, we take advantages of nano-techniques to deliver TGF-β inhibitors LY2157299 (LY) towards the tumor sites, in order to help achieve a improved and long-term functions of CAR-T towards lymphoma. Based on amphipathic hydroxyethyl starch-polycaprolactone (HES-PCL), LY and photosensitizer indocyanine green (ICG) were co-loaded in HES-PCL to achieve LY/ [email protected] nanoparticle. The enhanced function of CAR-T benefited from LY/ [email protected] were verified through lymphoma Raji cells in vitro and Nod scid gamma mice engrafted with the Raji cells in vivo. LY was targeted transported to tumor site and accelerated release by mild ICG photothermal. Chemokines CXCL9/10/11 at the tumor site relevant to CAR-T migration and chemokines receptor CXCR3 of CAR-T could be up-regulated by LY, thus facilitated the enhanced accumulation of CAR-T at lymphoma site. T effector memory cells differentiation could also be accelerated by LY/ [email protected] Combined therapy of LY/ [email protected] and CAR-T achieved 2.4 times higher antitumor activity and 2.7 times higher relapse inhibiting rates than CAR-T alone within 15 days and 11 days, respectively. The results suggested that LY/ [email protected] facilitated the enhanced therapeutic index of CAR-T cells towards lymphoma simply and safely, it may be further potentiated applied for other solid tumors.
研究领域:
肿瘤学
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免疫治疗
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纳米技术
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
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IF 18.5
Lei Cao,Dongsheng Tang,Zhen Yu,Yue Shen,Yang Wang,Yue-Qin Li,Juan Chen,Zhao-Qian Liu,Ji-Ye Yin,Haihua Xiao,Xiang-Ping Li
Endogenous T cell activation relies on recognizing tumor-specific antigens. However, tumor cells often alter phenotypes to evade immune surveillance, resulting in immune escape and drug resistance. Photodynamic therapy (PDT) activates anti-tumor immune responses by generating reactive oxygen species, which induce endoplasmic reticulum stress and immunogenic cell death. The clinical application of PDT is limited by immunosuppressive tumor microenvironment. Notably, enhancer of zeste homolog 2 (EZH2) regulates expression of immune-related genes in tumor and immune cells through H3K27 methylation. Consequently, targeting EZH2-mediated epigenetic silence provides an effective strategy to enhance the anti-tumor immune effect of PDT. In this study, a nano-delivery system (NP2) is designed to demonstrate PDT and epigenetic reprogramming effects. NP2 can reverse epigenetic silence, enhance MHC-I expression, and induce release of CXCL9-10 via EZH2i. Meanwhile, NP2 has a significant effect on PDT, inducing endoplasmic reticulum stress that resulted in immunogenic cell death and subsequent activation of the immune cascade. In a mouse model of in situ breast cancer, the combination of PDT activation and epigenetic reprogramming through EZH2i showed synergistic effects on remolding, and triggering a robust anti-tumor immune response in vivo. This study provides a novel idea for improving the immunosuppressive environment in clinical individualized immunotherapy.
研究领域:
癌症生物学
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免疫学
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纳米技术
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药理学
✓ 已验证
产品关联
DOI
高影响因子
eLife
·
2024
·
IF 6.4
Youxi Liu,Meimei Yin,Xiaoting Mao,Shuai Wu,Shuangping Wei,Shujun Heng,Yichun Yang,Jinwen Huang,Zhuolin Guo,Chuan Li,Chao Ji,Liu Hu,Wenjie Liu,Ling-juan Zhang
Allergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4+ or CD8+ lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ+ lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion of Ifngr1 in dermal fibroblasts in mice reduced Cxcl9/10 expression, dermal infiltration of CD8+ T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ+ CD8+ T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis.
研究领域:
免疫学
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皮肤病学
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转录组学
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细胞生物学
✓ 已验证
DOI
高影响因子
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