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The gut microbiome modulate response to immunotherapy in cancer

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Science China Life Sciences 2024年

作者： Shan-Shan Jiang Zi-Ran Kang Ying-Xuan Chen Jing-Yuan Fang Division of Gastroenterology and Hepatology Shanghai Institute of Digestive Disease NHC Key Laboratory of Digestive Diseases State Key Laboratory for Oncogenes and Related Genes Renji Hospital School of Medicine Shanghai Jiao Tong University

Gut microbiota have been reported to play an important role in the occurrence and development of malignant tumors. Currently, clinical studies have identified specific gut microbiota and its metabolites associated with efficacy of immunotherapy in multiple types of *** investigations have elucidated that gut microbiota modulate the antitumor immunity and affect the efficacy of cancer immunotherapy. Certain microbiota and its metabolites may favorably remodel the tumor microenvironment by engaging innate and/or adaptive immune cells. Understanding how the gut microbiome interacts with cancer immunotherapy opens new avenues for improving treatment strategies. Fecal microbial transplants, probiotics, dietary interventions, and other strategies targeting the microbiota have shown promise in preclinical studies to enhance the immunotherapy. Ongoing clinical trials are evaluating these approaches. This review presents the recent advancements in understanding the dynamic interplay among the host immunity, the microbiome, and cancer immunotherapy, as well as strategies for modulating the microbiome, with a view to translating into clinical applications.

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The crosstalk between enteric nervous system and immune system in intestinal development,homeostasis and diseases

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Science China(Life Sciences) 2024年第1期67卷 41-50页

作者： Xindi Wang Chenbo Ding Hua-Bing Li Shanghai Institute of Immunology State Key Laboratory of Oncogenes and Related GenesShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism Shanghai Jiao Tong University School of MedicineShanghai 200025China

The gut is the largest digestive and absorptive organ,which is essential for induction of mucosal and systemic immune responses,and maintenance of metabolic-immune *** intestinal components contain the epithelium,stromal cells,immune cells,and enteric nervous system(ENS),as well as the outers,such as gut microbiota,metabolites,and *** dyshomeostasis of intestinal microenvironment induces abnormal intestinal development and functions,even colon diseases including dysplasia,inflammation and *** recent studies have identified that ENS plays a crucial role in maintaining the immune homeostasis of gastrointestinal(GI)*** crosstalk between ENS and immune cells,mainly macrophages,T cells,and innate lymphoid cells(ILCs),has been found to exert important regulatory roles in intestinal tissue programming,homeostasis,function,and *** this review,we mainly summarize the critical roles of the interactions between ENS and immune cells in intestinal homeostasis during intestinal development and diseases progression,to provide theoretical bases and ideas for the exploration of immunotherapy for gastrointestinal diseases with the ENS as potential novel targets.

关键词： enteric nervous system macrophages T cells innate lymphoid cells neuro-immune interactions

STAT3-Dependent Effects of Polymeric Immunoglobulin Receptor in Regulating Interleukin-17 Signaling and Preventing Autoimmune Hepatitis

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Engineering 2024年第5期36卷 209-222页

作者： Ting Li Tongtong Pan Nannan Zheng Xiong Ma Xiaodong Wang Fang Yan Huimian Jiang Yuxin Wang Hongwei Lin Jing Lin Huadong Zhang Jia Huang Lingming Kong Anmin Huang Qingxiu Liu Yongping Chen Dazhi Chen Hepatology Diagnosis and Treatment Center The First Affiliated Hospital of Wenzhou Medical University&Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver DiseasesWenzhou 325035China Department of Clinical Medicine Hangzhou Medical CollegeHangzhou 310053China state key laboratory for oncogenes and related genes Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200001China Wenzhou Medical University Wenzhou 325035China Division of Infectious Diseases Lishui People’s HospitalLishui 323000China

One-third of patients with autoimmune hepatitis(AIH)have cirrhosis at the time of *** relevance of these variables,although unknown,is believed to be critical in AIH because of suspected interactions between the gut microbiome and genetic *** of the gut flora and elevated polymeric immunoglobulin receptor(pIgR)levels have been observed in both patients and mouse ***,there is a direct relationship between pIgR expression and transaminase levels in patients with *** this study,we aimed to explore how pIgR influences the secretion of regenerating islet-derived 3 beta(Reg3b)and the flora composition in AIH using in vivo experiments involving patients with AIH and a concanavalin A-induced mouse model of ***3b expression was reduced in pIgR gene(Pigr)-knockout mice compared to that in wild-type mice,leading to increased microbiota ***,exogenous pIgR supplementation increased Reg3b expression and maintained microbiota *** sequencing revealed the participation of the interleukin(IL)-17 signaling pathway in the regulation of Reg3b through ***,the introduction of external pIgR could not restore the imbalance in gut microbiota in AIH,and the decrease in Reg3b expression was not apparent following the inhibition of signal transducer and activator of transcription 3(STAT3).In this study,pIgR facilitated the upregulation of Reg3b via the STAT3 pathway,which plays a crucial role in preserving the balance of the intestinal microbiota in *** this research,we discovered new molecular targets that can be used for the diagnosis and treatment of AIH.

关键词： Autoimmune hepatitis Polymeric immunoglobulin receptor Regenerating islet-derived 3 beta Intestinal microbiota Signal transducer and activator of transcription 3

Molecular mechanisms of DNA lesion and repair during antibody somatic hypermutation

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Science China Life Sciences 2024年

作者： Qian Hao Jinfeng Li Leng-Siew Yeap Shanghai Institute of Immunology Department of Immunology and Microbiology State Key Laboratory of Oncogenes and Related Genes Shanghai Jiao Tong University School of Medicine Center for Immune-related Diseases at Shanghai Institute of Immunology Department of Endocrinology and Metabolic Diseases Ruijin Hospital Shanghai Jiao Tong University School of Medicine

Antibody diversification is essential for an effective immune response, with somatic hypermutation(SHM) serving as a key molecular process in this adaptation. Activation-induced cytidine deaminase(AID) initiates SHM by inducing DNA lesions, which are ultimately resolved into point mutations, as well as small insertions and deletions(indels). These mutational outcomes contribute to antibody affinity *** mechanisms responsible for generating point mutations and indels involve the base excision repair(BER) and mismatch repair(MMR)pathways, which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur. In this regard,translesion synthesis(TLS) polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions. This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM. Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies(bnAbs) and autoantibodies, and has implications for vaccine design and therapeutics.

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FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis

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Acta Pharmaceutica Sinica B 2024年第6期14卷 1605-1623页

作者： Zhifeng Huang Tongtong Pan Liang Xu Lu Shi Xiong Ma Liya Zhou Luyao Wang Jiaojiao Wang Guoqing Zhu Dazhi Chen Lingtao Song Xiaomin Pan Xiaodong Wang Xiaokun Li Yongde Luo Yongping Chen Hepatology Diagnosis and Treatment Center Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseasesthe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325035China Oujiang laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)&School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhou 325035China School of laboratory Medicine and Life Sciences Wenzhou Medical University&Key Laboratory of Laboratory MedicineMinistry of EducationWenzhou Medical UniversityWenzhou 325035China Division of Gastroenterology and Hepatology Key Laboratory of Gastroenterology and HepatologyMinistry of HealthState Key Laboratory for Oncogenes and Related GenesRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200001China Hangzhou Medical College Hangzhou 311300China

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine;however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca^(2+)/calmodulin-dependent protein kinasekinase 2 (CaMKKβ) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

关键词： Fibroblast growthfactor 4 Fibroblast growth factor receptor 4 Immune liver injury Ca^(2+)/Calmodulin dependent protein

Enhancing immunotherapy efficacy against MHC-I deficient triple-negative breast cancer using LCL161-loaded macrophage membranedecorated nanoparticles

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3218-3231页

作者： Wen Zhang Yihui Zhai Ying Cai Xiang Gong Yunxuan Jiang Rong Rong Chao Zheng Binyu Zhu Helen He Zhu Hao Wang Yaping Li Pengcheng Zhang China state Institute of Pharmaceutical Industry Shanghai 201203China state key laboratory of Drug Research&Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Biomedical Engineering&state key laboratory of Advanced Medical Materials and Devices ShanghaiTech UniversityShanghai 201210China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China Yantai Institute of Materia Medica Shandong 264000China state key laboratory of oncogenes and related genes Renji-Med-X Stem Cell Research CenterDepartment of UrologyRen Ji HospitalSchool of Medicine and School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai 200127China University of Chinese Academy of Sciences Beijing 100049China

Current cytotoxic T lymphocyte(CTL)activating immunotherapy requires a major histocompatibility complex I(MHC-I)-mediated presentation of tumor-associated antigens,which malfunctions in around half of patients with triple-negative breast cancer(TNBC).Here,we create a LCL161-loaded macrophage membrane decorated nanoparticle(LMN)for immunotherapy of MHC-I-deficient *** on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161,which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer *** released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 *** also block CD47-mediated phagocytosis *** inhibit the growth of MHC-I-deficient TNBC tumors,as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel,and prolong the survival of animals,during which process CTLs also play important *** macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophagemediated antitumor immunity for effective immunotherapy of MHC-I-deficient cancers.

关键词： MHC-I deficiency Macrophage CD47 Immunotherapy Triple-negative breast cancer Phagocytosis Immune checkpoint Innate immunity

Genomic profiling of colorectal cancer in large-scale Chinese patients:amplification and somatic mutations in ERBB2

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Oncology Research 2024年第9期32卷 1429-1438页

作者： YUZHI LIU EVELYNE BISCHOF ZHIQIN CHEN JIAHUAN ZHOU BEI ZHANG DING ZHANG YONG GAO MING QUAN Department of Oncology Shanghai East HospitalTongji University School of MedicineShanghaiChina state key laboratory of oncogenes and related genes Shanghai Cancer InstituteDepartment of OncologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Jiangsu Hengrui Pharmaceuticals Co. Ltd.ShanghaiChina D Medicines Inc. ShanghaiChina

Objectives:Human epidermal growth factor receptor 2(HER2)-targeted therapies have demonstrated potential benefits for metastatic colorectal cancer(mCRC)patients with HER2 amplification,but are not satisfactory in cases of HER2 mutant ***:Consequently,further elucidation of amplifications and somatic mutations in erythroblastic oncogene B-2(ERBB2)is *** genomic profiling was conducted on 2454 Chinese CRC cases to evaluate genomic alterations in 733 cancer-related genes,tumor mutational burden,microsatellite instability,and programmed death ligand 1(PD-L1)***:Among 2454 CRC patients,85 cases(3.46%)exhibited ERBB2 amplification,and 55 cases(2.24%)carried ERBB2 mutation.p.R678Q(28%),p.V8421(24%),and p.S310F/Y(12%)were the most prevalent of the 16 detected mutation *** comparison to the ERBB2 altered(alt)group,KRAS/BRAF mutations were more prevalent in ERBB2 wild-type(wt)samples(ERBB2wt ***2alt,KRAS:50.9%vs.25.6%,pgenes varied between ERBB2 copy number variation(CNV)and ERBB2 single nucleotide variant(SNV);TP53 alterations tended to co-occur with ERBB2 amplification(92.3%)as opposed to ERBB2 mutation(58.3%).KRAS and PIK3CA alterations were more prevalent in ERBB2 SNV cases(KRAS/PIK3CA:45.8%/31.2%)compared to ERBB2 amplification cases(KRAS/PIK3CA:14.1%/7.7%).Conclusion:Our study delineates the landscape of HER2 alterations in a large-scale cohort of CRC patients from *** findings enhance our understanding of the molecular features of Chinese CRC patients and offer valuable implications for further investigation.

关键词： Colorectal cancer ERBB2 HER2 Human epidermal growth factor receptor 2 Genetic profiling Precision oncology

The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer

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Research 2024年第1期2023卷 119-130页

作者： Ding Ding Haitao Zhao Dali Wei Qinglai Yang Cai Yang Ruowen Wang Yumei Chen Lianghua Li Shuxian An Qian Xia Gang Huang Jianjun Liu Zeyu Xiao Weihong Tan Institute of Molecular Medicine(IMM) Renji HospitalState Key Laboratory of Oncogenes and Related GenesShanghai Jiao Tong University School of Medicineand College of Chemistry and Chemical EngineeringShanghai Jiao Tong UniversityShanghai 200240China Department of Nuclear Medicine Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China Center for Molecular Imaging Probes Cancer Research InstituteUniversity of South ChinaHengyangHunan 421001China The key laboratory of Zhejiang Province for Aptamers and Theranostics Zhejiang Cancer HospitalHangzhou Institute of Medicine(HIM)Chinese Academy of SciencesHangzhouZhejiang 310022China Molecular Science and Biomedicine laboratory(MBL) State Key Laboratory of Chemo/Biosensing and ChemometricsCollege of Chemistry and Chemical EngineeringHunan UniversityChangshaHunan 410082China Shanghai key laboratory of Molecular Imaging Shanghai University of Medicine and Health SciencesShanghai 201318China Department of Pharmacology and Chemical Biology Shanghai Jiao Tong University School of MedicineShanghai200127China

Serving as targeting ligands,aptamers have shown promise in precision ***,the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’clinical *** bridge this gap,here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68(^(68)Ga)radiolabeled *** specificity and binding affinity of a radiolabeled aptamer,named ^(68)Ga[Ga]-NOTA-SGC8,were maintained as proven in *** preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity,potential mutation risks,or genotoxicity at high dosage(40 mg/kg).Based on this result,a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles,as well as biosafety,of the radiolabeled SGC8 aptamer in the human *** advantage of the cutting-edge total-body PET,the aptamers’distribution pattern in the human body was acquired in a dynamic fashion.

关键词： metabolism dosage Whole

Topological reorganization and functional alteration of distinct genomic components in gallbladder cancer

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Frontiers of Medicine 2024年第1期18卷 109-127页

作者： Guoqiang Li Peng Pu Mengqiao Pan Xiaoling Weng Shimei Qiu Yiming Li Sk Jahir Abbas Lu Zou Ke Liu Zheng Wang Ziyu Shao Lin Jiang Wenguang Wu Yun Liu Rong Shao Fatao Liu Yingbin Liu Department of Biliary-Pancreatic Surgery Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200127China state key laboratory of oncogenes and related genes Shanghai Cancer InstituteShanghai200127China Shanghai key laboratory of Biliary Tract Disease Shanghai200082China Department of Health Science and Engineering University of Shanghai for Science and TechnologyShanghai200082China Shanghai Tenth People’s Hospital of Tongji University Shanghai200072China Department of General Surgery Xinhua HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200082China Department of Pharmacology Shanghai Jiao Tong University School of MedicineShanghai200025China

Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human ***,knowledge of the topological rearrangement of genomic hierarchical layers in cancer is largely ***,by taking advantage of in situ Hi-C,RNA-sequencing,and chromatin immunoprecipitation sequencing(ChIP-seq),we investigated structural reorganization and functional changes in chromosomal compartments,topologically associated domains(TADs),and CCCTC binding factor(CTCF)-mediated loops in gallbladder cancer(GBC)tissues and cell *** observed that the chromosomal compartment A/B switch was correlated with CTCF binding levels and gene expression *** inter-TAD interactions with weaker TAD boundaries were identified in cancer cell lines relative to normal ***,the chromatin short loops and cancer unique loops associated with chromatin remodeling and epithelial–mesenchymal transition activation were enriched in cancer compared with their control ***-specific enhancer–promoter loops,which contain multiple transcription factor binding motifs,acted as a central element to regulate aberrant gene *** of individual enhancers in each loop anchor that connects with promoters led to the inhibition of their corresponding gene ***,our data offer the landscape of hierarchical layers of cancer genome and functional alterations that contribute to the development of GBC.

关键词： 3D genome cancer TADs loop gene regulation