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Targeting innate sensing in the tumor microenvironment to improve immunotherapy

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Cellular & Molecular Immunology 2020年第1期17卷 13-26页

作者： Zhida Liu yang-xin fu Department of Pathology UT Southwestern Medical CenterDallasTX 75235USA Department of Immunology UT Southwestern Medical CenterDallasTX 75235USA

The innate immune sensing pathways play critical roles in the defense against pathogen infection,but their roles in cancer immunosurveillance and cancer therapies are less *** propose that defective innate immune sensing inside the tumor microenvironment might limit T-cell responses to immunotherapy.A recent mechanistic understanding of conventional therapies revealed that both innate immune sensing and T-cell responses are essential for optimal antitumor efficacy.T-cell-based immunotherapy,particularly immune checkpoint blockade,has achieved great success in reactivating antitumor immune responses to lead to tumor regression,but only in a small fraction of ***,incorporating conventional therapy that can increase innate sensing and immunotherapy should lead to promising strategies for cancer ***,we review the innate sensing pathways related to cancer initiation/progression and therapies,summarize the recent key findings in innate immune sensing related to conventional therapies,evaluate current combination strategies,and highlight the potential issues of combinational therapies in terms of antitumor efficacy and toxicities.

关键词： Innate immune sensing Conventional therapy Immunotherapy

New immune therapy targets tumor-associated environment:from bone marrow to tumor site

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Cellular & Molecular Immunology 2012年第1期9卷 1-2页

作者： yang-xin fu Department of Pathology and Committee on Immunology University of ChicagoChicagoILUSA

Tumor-associated antigens(TAAs)and immune cells coexist in the tumor ***,spontaneously developed cancer cells have coevolved with immune cells,and have utilized inflammatory signals and immune suppressive mechanisms to support and promote tumor *** immune suppressive mechanisms and induction of potent and lasting anti-tumor immunity is the goal of cancer vaccination and *** that there are vast numbers of genetic changes associated with carcinogenesis,it would not be unexpected that tumor cells express considerable neoantigens,and many cancers are immunogeneic.1,2 Nonetheless,spontaneous tumor eradication is *** many tissue-specific proteins or tumor neoproteins are used as vaccines or antigens to prime and expand TAA-specific T cells,our knowledge of tumor rejecting antigens remains limited.

关键词： immunity antigens cancer

Degradation of CTLA-4 balances toxicity and efficacy

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Science Bulletin 2019年第19期64卷 1388-1389页

作者： Zhenhua Ren yang-xin fu The Department of Pathology UT Southwestern Medical CenterDallasTX75235-9072USA The Department of Immunology UT Southwestern Medical CenterDallasTX75235-9072USA

The notorious side effects of anti-CTLA-4 limit its use in the clinic,but what causes the severe side effects remains largely *** et al.[1]elucidated antibody-induced CTLA-4lysosomal degradation as a new mechanism accounting for the severe immunotherapy-related adverse effects and limited efficacy of anti-CTLA-4 ***-4 expresses on regulatory T cells(Tregs)and activated CD8 and CD4 effector cells.

关键词： Degradation CTLA-4 toxicity

Targeting and utilizing primary tumors as live vaccines:changing strategies

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Cellular & Molecular Immunology 2012年第1期9卷 20-26页

作者： Xuanming yang Eric D Mortenson yang-xin fu Department of Pathology and Committee on Immunology University of ChicagoChicagoILUSA

Tumor metastases and relapse are the major causes of morbidity and mortality in *** surgery,chemotherapy and/or radiation therapy can typically control primary tumor growth,metastatic and relapsing tumors are often inaccessible or resistant to these *** adaptive immune response can be generated during these conventional treatments of the primary tumor,and presumably both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune ***,when established,this response should be able to control metastatic growth and tumor *** review summarizes the mechanisms by which antitumor immune responses are generated,and recent findings supporting the hypothesis that many therapies targeting primary tumors can generate antitumor adaptive immune responses to prevent metastases and tumor relapse.

关键词： chemotherapy immunotherapy metastasis radiotherapy tumor vaccine

Inactivation of TGF-βsignaling in CAR-T cells

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Cellular & Molecular Immunology 2024年第3期21卷 309-310页

作者： Zaopeng yang yang-xin fu Changping Laboratory Beijing102206China Department of Basic Medical Sciences School of MedicineTsinghua UniversityBeijing100084China

Accumulating evidence suggests that the transforming growth factor(TGF)-βpathway might be an ideal target for optimizing chimeric antigen receptor(CAR)-T-cell therapy for solid *** Cellular&Molecular Immunology,Liang et al.(2024)reported that CAR-T cells expressing SMAD7 displayed favorable antitumor efficacy and a reduced risk of systemic toxicity.

关键词： CAR Immunology

Lymphotoxin signalling in tertiary lymphoid structures and immunotherapy

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Cellular & Molecular Immunology 2017年第10期14卷 809-818页

作者： Haidong Tang Mingzhao Zhu Jian Qiao yang-xin fu Department of Pathology University of TexasSouthwestern Medical CenterDallasTX 75235USA IBP-UTSW Joint Immunotherapy Group Chinese Academy of ScienceKey Laboratory for Infection and ImmunityInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China

Tertiary lymphoid structures(TLS)often develop at sites of persistent inflammation,including cancers and autoimmune *** most cases,the presence of TLS correlates with active immune *** of their proximity to pathological loci,TLS are an intriguing target for the manipulation of immune *** several years,it has become clear that lymphotoxin(LT)signalling plays critical roles in lymphoid tissue organogenesis and *** the current review,we will discuss the role of LT signalling in the development of *** a focus on cancers and autoimmune diseases,we will highlight the correlations between TLS and disease *** will also discuss the current efforts and potential directions for manipulating TLS for immunotherapies.

关键词： autoimmune disease cancer immunotherapy lymphotoxin signalling tertiary lymphoid structure

A mouse model for HBV immunotolerance and immunotherapy

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Cellular & Molecular Immunology 2014年第1期11卷 71-78页

作者： Dan yang Longchao Liu Danming Zhu Hua Peng Lishan Su yang-xin fu Liguo Zhang BP-UC Group for Immunotherapy CAS Key Laboratory for Infection and Immunity Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100049 China Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill NC USA Department of Pathology the University of Chicago 924E 57 Street Chicago IL60637

Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus （HBV） infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus （AAV） carrying a replicable HBV genome （AAV/ HBV）. Similar to the clinical HBV carriers, the mice infected with AAV/H BV were sero-negative for antibodies against HBV surface antigen （HBsAg）. Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response against HBV in these mice. To identify a vaccine that can potentially circumvent this tolerance, the TLR9 agonist CpG was added to HBsAg as an adjuvant. Vaccination of mice with HBsAg/CpG induced not only clearance of viremia, but also strong antibody production and T-cell responses. furthermore, both the DNA replication and protein expression of HBV were significantly reduced in the livers of AAV/H BV-infected mice. Accordingly, AAV/HBV-infected mice may be used as a robust model for investigating the underlying mechanism（s） of HBV immunotolerance and for developing novel immunotherapies to eradicate HBV infections.

关键词： AAV vector HBV immunotherapy immunotolerance mouse model

Mucosal vaccine development for respiratory viral infections

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hLife 2024年第2期2卷 50-63页

作者： Yifan Lin Zhenxiang Hu yang-xin fu Hua Peng Department of Basic Medical Sciences School of MedicineTsinghua UniversityBeijingChina LivzonBio Inc. GuangdongChina Guangzhou Laboratory Guangzhou International Bio IslandGuangdongChina

Mucosal vaccines have risen to prominence in the corona virus disease 2019(COVID-19)pandemic due to their ability to elicit both local antibody and tissue-resident T cell responses,affording a dual-layered defense against infection and transmission at respiratory entry *** intramuscular vaccines predominantly focus on systemic immunity,mucosal vaccines offer a more nuanced,site-specific ***,the field faces a dearth of mucosal vaccine options for respiratory diseases,starkly contrasting to the extensive array of well-characterized injectable *** unique features of mucosal surfaces necessitate specialized adjuvants and delivery systems,adding complexity to adapting injectable vaccine technologies for mucosal ***,we review the recent insights into the specificities of respiratory mucosal immunology that provide a foundation for future innovations besides the emerging vaccine platforms,newly discovered adjuvants,and vaccine delivery systems,which may open promising avenues for developing mucosal vaccines targeting respiratory pathogens.

关键词： mucosal immunology respiratory viruses vaccine adjuvants

The tumor immunosuppressive microenvironment impairs the therapy of anti-HER2/neu antibody

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Protein & Cell 2012年第6期3卷 441-449页

作者： Meng Xu Xuexiang Du Mingyue Liu Sirui Li Xiaozhu Li yang-xin fu Shengdian Wang Key Laboratory of Infection and Immunity Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Graduate School of the Chinese Academy of Sciences Chinese Academy of SciencesBeijing 100049China Department of Pathology and Committee on Immunology University of ChicagoChicagoIL 60637USA

It has been well established that immune surveillance plays critical roles in preventing the occurrence and prog-ression of *** and more evidence in recent years showed the host anti-tumor immune responses also play important roles in the chemotherapy and radiotherapy of *** previous study found that tumor-targeting therapy of anti-HER2/neu mAb is mediated by CD8+T cell ***,we found here that enhancement of CD8+T cell responses by combination therapy with IL-15R/IL-15 fusion protein or anti-CD40,which are strong stimultors for T cell responses,failed to promote the tumor therapeutic effects of anti-HER2/neu *** of tumor microenviornment showed that tumor tissues were heavily infiltrated with the immunosuppressive macrophages and most tumor infiltrating T cells,especially CD8^(+)T cells,expressed high level of inhibitory co-signaling receptor *** data suggest that tumor microenvironment is dominated by the immunosuppressive strategies,which thwart anti-tumor immune ***,the successful tumor therapy should be the removal of inhibitory signals in the tumor microenvir-onment in combination with other therapeutic strategies.

关键词： anti-HER2/neu antibody CD8^(+)T cells tu-mor microenvironment tumor therapy immune suppression