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Interaction between HLA-G and NK cell receptor KIR2DL4 orchestrates HER2-positive breast cancer resistance to trastuzumab

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Signal Transduction and Targeted Therapy 2021年第7期6卷 2210-2224页

作者： Guoxu Zheng Zhangyan Guo Weimiao Li Wenjin Xi baile zuo Rui Zhang Weihong Wen An-Gang Yang Lintao Jia State Key Laboratory of Cancer Biology Department of ImmunologyFourth Military Medical UniversityXi'anChina Department of Oncology The Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina State Key Laboratory of Cancer Biology Department of Biochemistry and Molecular BiologyFourth Military Medical UniversityXi’anChina

Despite the successful use of the humanized monoclonal antibody trastuzumab(Herceptin)in the clinical treatment of human epidermal growth factor receptor 2(HER2)-overexpressing breast cancer,the frequently occurring drug resistance remains to be *** regulatory mechanisms of trastuzumab-elicited immune response in the tumor microenvironment remain largely ***,we found that the nonclassical histocompatibility antigen HLA-G desensitizes breast cancer cells to trastuzumab by binding to the natural killer(NK)cell receptor *** engaged by HLA-G,KIR2DL4 promotes antibody-dependent cell-mediated cytotoxicity and forms a regulatory circuit with the interferon-γ(IFN-γ)production pathway,in which IFN-γ upregulates KIR2DL4 via JAK2/STAT1 signaling,and then KIR2DL4 synergizes with the Fey receptor to increase IFN-γ secretion by NK *** treatment of neoplastic and NK cells leads to aberrant cytokine production characterized by excessive tumor growth factor-β(TGF-β)and IFN-γ,which subsequently reinforce HLA-G/KIR2DL4 *** addition,TGF-β and IFN-γ impair the cytotoxicity of NK cells by upregulating PD-L1 on tumor cells and PD-1 on NK *** of HLA-G/KIR2DL4 signaling improved the vulnerability of HER2-positive breast cancer to trastuzumab treatment in *** findings provide novel insights into the mechanisms underlying trastuzumab resistance and demonstrate the applicability of combined HLA-G and PD-L1/PD-1 targeting in the treatment of trastuzumab-resistant breast cancer.

关键词： KIR2DL4 trastuzumab treatment

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SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors

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Cellular & Molecular Immunology 2024年第3期21卷 213-226页

作者： Sixin Liang Rui Zheng baile zuo Jia Li Yiyi Wang Yujie Han Hao Dong Xiaojuan Zhao Yiting Zhang Pengju Wang Ruotong Meng Lintao Jia Angang Yang Bo Yan State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Department of Biochemistry and Molecular BiologyFourth Military Medical UniversityXi’anShaanxi710032China School of Medicine Technology Xinxiang Medical UniversityXinxiangHenan453003China Department of Obstetrics and Gynecology Xijing Hospital of Fourth Military Medical UniversityXi’anShaanxi710032China College of Life Science Yan’an UniversityYan’anShaanxi716000China Department of Immunology Fourth Military Medical UniversityXi’anShaanxi710032China

Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment(TME)and systemic toxicity caused by excessive cytokine *** a key regulator of the immunosuppressive TME,TGF-βpromotes cytokine synthesis via the NF-κB ***,we coexpressed SMAD7,a suppressor of TGF-βsignaling,with a HER2-targeted CAR in engineered T *** novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion,which enabled sustained tumoricidal capacity after continuous antigen ***,SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T ***,SMAD7 downregulated TGF-βreceptor I and abrogated the interplay between the TGF-βand NF-κB pathways in CAR-T *** a result,these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β.SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor ***,our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.

关键词： TGF-βpathway SMAD7 NF-κB pathway CAR-T-cell therapy Cytokine release syndrome(CRS)

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High expression of CREPT promotes tumor growth and is correlated with poor prognosis in colorectal cancer

High expression of CREPT promotes tumor growth and is correl...

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第十一届全国免疫学学术大会

作者： Zheng guoxu zuo baile Guo zhangyan Xi wenjin Wen weihong Yang angang State key laboratory of Cancer Biology Department of ImmunologyFourth Military Medical University

Background: CREPT(cell cycle-related and expression elevated protein in tumor) is highly expressed in many kinds of cancer, and has been shown to be prognostic in certain cancers. However, the clinical significance of CREPT in colorectal cancer(CRC) has not been sufficiently investigated. Methods: In this study, we examined the CREPT expression by IHC in a tissue array composed of 225 clinical CRC tissues and adjacent normal tissues, and analyzed the correlation between CREPT expression and other clinicopathological features. We also evaluated the biological function of CREPT both in vitro and in vivo using knockdown or overexpressing CRC cells. Results: Our results showed that CREPT expressed in 175 of 225(77.8%) CRC patients and the CREPT expression was significantly associated with tumor differentiation(P=0.000), Dukes’ stages(P=0.013) and metastasis(P=0.038). Patients with high CREPT expression tended to have shorter survival time. Multivariate analysis showed that positive CREPT expression can be used as an independent predictor for CRC prognosis. CREPT knockdown cells showed inhibited cell proliferation and arrested cell cycle, while CREPT overexpressing cells showed increased proliferation and promoted cell cycle. In addition, CREPT overexpression significantly promoted tumor growth in vivo. Mechanism study showed that CREPT may regulate cell proliferation and cell cycle through the regulation on cyclin D3, CDK4 and ***: CREPT was highly expressed in CRC tissues, and the elevated CREPT expression is significantly correlated with the aggressive phenotype and poor prognosis of CRC. CREPT might regulate cell proliferation and cell cycle arrest through the regulation on the expression of cyclin D3, CDK4 and CDK6. Thus, we hypothesize that CREPT could be a promising target and potential prognostic indicator in CRC.

关键词： CREPT cell proliferation cell cycle colorectal cancer prognosis

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Combined treatment with valproic acid and 5-Aza-2'-deoxycytidine synergistically inhibits human clear cell renal cell carcinoma growth and migration

Combined treatment with valproic acid and 5-Aza-2'-deoxycyti...

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第十二届全国免疫学学术大会

作者： Xi Wenjin Chen Xu Lin Zhifeng zuo baile Wang Wei Wu Jieheng Yang Angang Wang Tao Department of Immunology Fourth Military Medical University Fourth Military Medical University Department of Medical Genetics and Developmental Biology Fourth Military Medical University

Background:Histone acetylation and DNA methylation are important mammalian epigenetic modifications that participate in the regulation of gene *** dysregulation of histone deacetylase and DNA methyltransferases are hallmarks of malignancy,they have become promising therapeutic *** this study,we explored the antitumor activity of valproic acid(VPA),a histone deacetylase inhibitor(HDACi) and 5-Aza-2’-deoxycytidine(5-Aza),an inhibitor of DNA methyltransferases,on renal cell carcinoma(RCC) cell lines 786-0 and ***:To analyze the impact of VPA,5-Aza and their combination on ***:The cell proliferation was detected by xCELLigence RTCA DP Instrument,viability by CCK8 assay,cell apoptosis and cell cycle by flow cytometry,and cell migration by wound healing assay,transwell assay and xCELLigence RTCA DP ***:We discovered that VPA and 5-Aza could individually induce decreased viability and have an inhibitory effect on the proliferation of 786-0 and 769-P *** anti-growth effect was more pronounced when the cells were treated with both VPA and *** combination of VPA and 5-Aza also elicited more apoptosis and produced more cell cycle arrest in the G1 phase for both cell *** the other hand,treatment of RCC cells with VPA,5-Aza,or a combination of both resulted in slow wound healing and impaired ***:These findings clearly demonstrated that VPA combined with 5-Aza could significantly increase anti-RCC effects by inhibiting cellular proliferation,inducing apoptosis,promoting cell cycle arrest and prohibiting the migration of human RCC cells.

关键词： Valproic acid 5-Aza-2’-deoxycytidine Renal cell carcinoma Proliferation Migration

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30 GHz GeSn photodetector on SOI substrate for 2 µm wavelength application

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Photonics Research 2021年第4期9卷 494-500页

作者： Xiuli Li Linzhi Peng Zhi Liu Zhiqi Zhou Jun Zheng Chunlai Xue Yuhua zuo baile Chen Buwen Cheng State Key Laboratory on Integrated Optoelectronics Institute of SemiconductorsChinese Academy of SciencesBeijing 100083China Center of Materials Science and Optoelectronics Engineering University of Chinese Academy of SciencesBeijing 100049China School of Information Science and Technology ShanghaiTech UniversityShanghai 201210China Beijing Academy of Quantum Information Sciences Beijing 100193China

We report the demonstration of a normal-incidence p-i-n germanium-tin(Ge_(0.951)Sn_(0.049))photodetector on silicon-on-insulator substrate for 2μm wavelength *** DC and RF characteristics of the devices have been characterized.A dark current density under−1 V bias of approximately 125 mA/cm^(2) is achieved at room temperature,and the optical responsivity of 14 mA/W is realized for illumination wavelength of 2μm under−1 V reverse *** addition,a 3 dB bandwidth(f_(3dB))of around 30 GHz is achieved at−3 V,which is the highest reported value among all group III–V and group IV photodetectors working in the 2μm wavelength *** work illustrates that a GeSn photodetector has great prospects in 2μm wavelength optical communication.

关键词： 2μm GeSn SOI

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