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Recent advances in cancer-associated fibroblast:Biomarkers,signaling pathways,and therapeutic opportunities

Chinese Medical Journal 2024年第6期137卷 638-650页

作者： Donger Zhou Lei Zheng Department of Hepatobiliary-Pancreatic Surgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Sidney kimmel Comprehensive Cancer Center The Skip Viragh Pancreatic Cancer Center for Clinical Research and Careand The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of MedicineBaltimoreMD 21287USA

Anti-cancer therapies usually focus on tumor cells,but non-tumor stromal components in the tumor microenvironment also play vital roles in tumor initiation and progression,which may be the prognostic factors and potential therapeutic ***-associated fibroblasts(CAFs)are the essential component in the tumor environment,exhibiting high heterogeneity in their cell origin and phenotype with diverse functions that influence tumor angiogenesis,immune systems,and ***-cell RNA sequencing and genetically engineered mouse models have increased our understanding of CAF diversity,and many subtypes have been ***,the precise functions of these subtypes need to be studied and *** of signaling pathways and epigenetic changes in CAFs facilitate understanding of the phenotypes of CAFs and the crosstalk between tumor cells and CAFs to provide potential therapeutic *** clinical trials,including phase III trials targeting CAFs,have been performed ***,few of these trials have generated promising results,which indicates that the complexity of CAFs in the tumor microenvironment remains largely unknown,and in-depth investigations of CAFs should be *** review summarizes the research on CAFs,focusing on the heterogeneity of their phenotypes and functions,specific signaling pathways,and the therapeutic strategies involving ***,we briefly discuss the current technologies commonly used in CAF studies and describe the challenges and future perspectives of CAF research.

关键词： Cancer-associated fibroblasts Tumor microenvironment Anti-cancer therapy Targeted therapy

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Interleukin-10 gives exhausted chimeric antigen receptor(CAR)T cells a second breath

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Cancer Communications 2024年第7期44卷 787-790页

作者： Christoph Heuser-Loy Leibniz institute for immunotherapy Division for Functional Immune Cell ModulationRegensburgGermany

Adoptive cell therapy(ACT)represents a major pillar of modern *** or synthetically endowed with the ability to recognize tumor-associated antigens,tumor-infiltrating lymphocytes(TILs)or T cells engineered to transgenically express T cell receptors or chimeric antigen receptors(CARs)are expanded and infused to tumor patients to lyse tumor ***,despite tremendous response rates against liquid tumors,many patients undergo relapses,and treatment outcomes in solid tumors have been disappointing so far[1].The harsh tumor microenvironment,including nutrient deprivation,acidification,hypoxia,and immunosuppressive signals[2,3],in conjunction with persistent antigen stimulation triggers a program of exhaustion in T cells(Figure 1A).Exhausted T cells exhibit reduced cytotoxicity and minimal proliferation potential,physiologically balancing tissue health with control of chronic viral infection or of tumor growth[4,5].Strategies to disengage or rewire the“erroneously”deployed exhaustion program to exploit the full potential of tumor-fighting T cells are highly sought after(Figure 1B).

关键词： Interleukin stimulation Figure

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CAR-T overdrive:harnessing inosine for metabolic rewiring and stemness induction

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2347-2348页

作者： MartíFarrera-Sal Michael Schmueck-Henneresse Berlin institute of Health(BIH)at Charité—Universitatsmedizin Berlin BIH Center for Regenerative Therapies(BCRT)Experimental ImmunotherapyAugustenburger Platz 1BerlinGermany

In a recent Cancer Cell publication,Klysz et *** the impact of inosine(INO),a catabolic product of adenosine(Ado),on Chimeric Antigen Receptor(CAR)T-cell function,stemness,and *** provided insights into T-cell exhaust... 详细信息

关键词： programming. CAR Ado

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Hepatic vein reconstruction during hepatectomy:A feasible and underused technique

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Hepatobiliary & Pancreatic Diseases International 2024年第4期23卷 421-427页

作者： Manish Ahuja Kunal Joshi Chris Coldham Paulo Muiesan Bobby Dasari Manuel Abradelo Ravi Marudanayagam Darius Mirza John Isaac David Bartlett Nikolaos A Chatzizacharias Robert P Sutcliffe Keith J Roberts Department of HPB and Liver Transplant Surgery University Hospitals Birmingham NHS Foundation TrustBirminghamUK institute of Immunology and immunotherapy University of BirminghamBirminghamUK

Complete surgical resection(R0)of liver tumors,primary or metastatic,remains the main objective in management of primary and metastatic liver tumors[1].Tumors invading to the proximity of the hepatic venous outflow pose a peculiar challenge to achieve R0 resections,because this location may render a tumor *** median survival of patients with liver tumor without surgery is less than 12 months[2].Even with surgery,post-hepatectomy liver failure and subsequently increased mortality are the main problems associated with complex resection[3].Moreover,when the vein is affected,vein resection and subsequent reconstruction are *** resection is a standard practice in liver resection and transplantation[4],for example,hepatic vein reconstruction during a living-donor liver transplant,porto-mesenteric axis reconstruction during resection of advanced pancreatic cancer and caval reconstruction during resection of retroperitoneal ***,novel techniques like total hepatic vascular exclusion(HVE)[5],veno-venous bypass[6]and ex vivo hepatic resection[7,8]have facilitated curative resections of tumors close to one or more major hepatic veins.

关键词： hepatectomy surgery mortality

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Gas-generating polymersomes-based amplified photoimmunotherapy for abscopal effect and tumor metastasis inhibition

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Chinese Chemical Letters 2024年第6期35卷 456-461页

作者： Chenlu Huang Xinyu Yang Qingyu Yu Linhua Zhang Dunwan Zhu Tianjin Key Laboratory of Biomedical Materials Key Laboratory of Biomaterials and Nanotechnology for Cancer ImmunotherapyInstitute of Biomedical EngineeringChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300192China

Due to the heterogeneity of tumors,single phototherapy cannot completely ablate tumors and inhibit tumor *** overcome these,we formulated targeted and multifunctional polymersomes ABC@ICGIMQ-LHRH(AIRL)that encapsulated Toll-like receptor(TLR)7/8 agonist imiquimod(IMQ)and photosensitizer indocyanine green(ICG)in the hydrophobic layer as well as bubble-generator NH_(4)HCO_(3) in the hydrophilic cavity to inhibit the growth of primary and distant tumors,and prevent tumor metastasis through synergistic *** AIRL polymersomes exhibited uniform and stable size,and high drug encapsulation efficiency,acid/reduction/laser responsiveness,excellent photothermal conversion efficiency,effective reactive oxygen species generation,high tumor *** could be effectively internalized by dendritic cells(DCs),achieve lysosome escape and enhance DCs *** synergistic photoimmunotherapy via AIRL polymersomes remarkably promoted the differentiation and activation of T cells,elevated strong systemic immune response to eradicate primary tumors and inhibit the growth of distant ***,the endurable immunological memory prevented tumor metastasis,which provided a promising nanoplatform for the combination therapy of cancer.

关键词： Polymersomes Phototherapy immunotherapy TLR 7/8 agonist Gas-generating

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The heterogeneity of tumor-associated macrophages and strategies to target it

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BIOCELL 2024年第3期48卷 363-378页

作者： HAO LV BO ZHU DEGAO CHEN institute of Cancer Xinqiao HospitalThird Military Medical UniversityChongqing400037China Chongqing Key Laboratory of immunotherapy Xinqiao HospitalThird Military Medical UniversityChongqing400037China

Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor *** studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical ***,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their ***,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor *** review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.

关键词： Tumor-associated macrophages Tissue-resident macrophages Heterogeneity Immune checkpoint therapy

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PD-1^(+)and TIM-3^(+)T cells widely express commonγ-chain cytokine receptors in multiple myeloma patients,and IL-2,IL-7,IL-15 stimulation up-regulates PD-1 and TIM-3 on T cells

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Oncology Research 2024年第10期32卷 1575-1587页

作者： EGOR V.BATOROV ALISA D.INESHINA TATIANA A.ARISTOVA VERA V.DENISOVA SVETLANA A.SIZIKOVA DARIA S.BATOROVA GALINA Y.USHAKOVA EKATERINA Y.SHEVELA ELENA R.CHERNYKH Laboratory of Cellular immunotherapy Research Institute of Fundamental and Clinical ImmunologyNovosibirsk630099Russia V.Zelman institute of Medicine and Psychology Novosibirsk National Research State UniversityNovosibirsk630090Russia Department of Hematology and Bone Marrow Transplantation Research Institute of Fundamental and Clinical ImmunologyNovosibirsk630099Russia

Background:Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma(MM)***,previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with commonγ-chain family cytokines in vitro and during homeostatic *** aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets upregulating PD-1 and TIM-3 checkpoint ***:The expression of CD25,CD122,CD127 commonγ-chain cytokine receptors,phosphorylated signal transducer and activator of transcription-5(pSTAT5)and eomesodermin(EOMES)was comparatively assessed with flow cytometry in PD-1-and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM ***:Substantial proportions of PD-1-and TIM-3-positive T lymphocytes expressed commonγ-chain cytokine receptors and *** of cytokine receptor expressing cells were significantly higher within TIM-3+T cells compared to PD-1+TIM-3−*** proportions of both PD-1-/TIM-3-negative and positive CD8+T cells express EOMES,while only moderate frequencies of CD4+PD-1+/TIM-3+T cells up-regulate this transcription ***,the surface presence of CD25 and intranuclear expression of EOMES in CD4+T cells were mutually exclusive regardless of PD-1 and TIM-3 *** stimulation with commonγ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+and TIM-3+T cell subsets in ***:Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine *** in commonγ-chain cytokine receptor expression between PD-1+and TIM-3+T cells may reflect functional dissimilarity of these cell *** blockade appears to alleviate lymphopenia-induced prolif

关键词： Autologous hematopoietic stem cell transplantation(AHSCT) CD25 CD122 Eomesodermin(EOMES) Homeostatic proliferation

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Exploring the Pathogenesis of Autoimmune Liver Diseases from the Heterogeneity of Target Cells

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Journal of Clinical and Translational Hepatology 2024年第7期12卷 659-666页

作者： Zi-Xuan Qiu Lin-Xiang Huang Xiao-Xiao Wang Zi-Long Wang Xiao-He Li Bo Feng Peking University People’s Hospital Peking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijing International Cooperation Base for Science and Technology on NAFLD DiagnosisBeijingChina

The incidence of autoimmune liver diseases(ALDs)and research on their pathogenesis are increasing ***,except for autoimmune hepatitis,which responds well to immunosuppression,primary biliary cholangitis and primary sclerosing cholangitis are insensitive to immunosuppressive *** the known effects of the environment,genetics,and immunity on ALDs,the heterogeneity of target cells provides new insights into their *** review started by exploring the heterogeneity in the development,structures,and functions of hepatocytes and epithelial cells of the small and large bile *** example,cytokeratin(CK)8 and CK18 are primarily expressed in hepatocytes,while CK7 and CK19 are primarily expressed in intrahepatic ***,emerging technologies of single-cell RNA sequencing and spatial transcriptomic are being applied to study *** review offered a new perspective on understanding the pathogenic mechanisms and potential treatment strategies for ALDs.

关键词： Autoimmune hepatitis Primary biliary cholangitis Primary sclerosing cholangitis Disease heterogeneity Single-cell RNA sequencing Pathogenesis

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Eosinophils promote CD8+ T cell memory generation to potentiate anti-bacterial immunity

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1230-1243页

作者： Jun Zhou Jiaqi Liu Bingjing Wang Nan Li Juan Liu Yanmei Han Xuetao Cao institute of Immunology Zhejiang University School of MedicineHangzhou 310058China National Key Laboratory of Immunity and Inflammation Institute of ImmunologyNaval Medical UniversityShanghai 200433China Department of Immunology Center for ImmunotherapyInstitute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005China institute of Immunology College of Life SciencesNankai UniversityTianjin 300071China

Memory CD8+T cell generation is crucial for pathogen elimination and effective vaccination against *** cellular and molecular circuitry that underlies the generation of memory CD8+T cells remains *** can modulate inflammatory allergic responses and interact with lymphocytes to regulate their functions in immune *** we report that eosinophils are required for the generation of memory CD8+T cells by inhibiting CD8+T cell ***-deficient mice display significantly impaired memory CD8+T cell response and weakened resistance against Listeria monocytogenes(L.m.)***,eosinophils secrete interleukin-4(IL-4)to inhibit JNK/Caspase-3 dependent apoptosis of CD8+T cells upon *** in ***,active eosinophils are recruited into the spleen and secrete more IL-4 to suppress CD8+T cell apoptosis during early stage of *** in *** transfer of wild-type(WT)eosinophils but not IL-4-deficient eosinophils into eosinophil-deficient mice could rescue the impaired CD8+T cell memory ***,our findings suggest that eosinophil-derived IL-4 promotes the generation of CD8+T cell memory and enhances immune defense against *** study reveals a new adjuvant role of eosinophils in memory T cell generation and provides clues for enhancing the vaccine potency via targeting eosinophils and related cytokines.

关键词： impaired immunity spleen

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LPA_(1) antagonist-derived LNPs deliver A20 mRNA and promote anti-fibrotic activities

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Nano Research 2024年第10期17卷 9095-9102页

作者： Jingyue Yan Diana D.Kang Chang Wang Xucheng Hou Shi Du Siyu Wang Yonger Xue Zhengwei Liu Haoyuan Li Yichen Zhong Binbin Deng David W.McComb Yizhou Dong Division of Pharmaceutics&Pharmacology College of PharmacyThe Ohio State UniversityColumbusOH 43210USA Icahn Genomics institute Precision Immunology InstituteDepartment of Immunology and ImmunotherapyDepartment of Oncological SciencesTisch Cancer InstituteBiomedical Engineering and Imaging InstituteFriedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkNY 10029USA Center for Electron Microscopy and Analysis The Ohio State UniversityColumbusOH 43212USA Department of Materials Science and Engineering The Ohio State UniversityColumbusOH 43210USA

Activated fibroblasts are major mediators of pulmonary *** are generally found in the connective tissue but upon activation can generate excess extracellular matrix(ECM)in the lung interstitial ***,fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis(IPF).Here,we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1(LPA_(1))and the inflammatory pathway through tumor necrosis factorα-induced protein 3(TNFAIP3,also known as A20)in ***,we synthesized a series of LPA_(1) antagonists,AM095 and AM966,derived amino lipids(LA lipids)which were formulated into LA-lipid nanoparticles(LA-LNPs)encapsulating ***,LA5-LNPs,with AM966 head group and biodegradable acetal lipid tails,showed efficient A20 mRNA delivery to lung fibroblasts in vitro(80.2%±1.5%)and ex vivo(17.2%±0.4%).When treated to primary mouse lung fibroblasts(MLF),this formulation inhibited fibroblast migration and collagen production,thereby slowing the progression of ***,LA5-LNPs encapsulated with A20 mRNA is a novel platform offering a potential approach to regulate fibroblast activation for the treatment of IPF.

关键词： lysophosphatidic acid receptor 1(LPA_(1))antagonist tumor necrosis factorα-induced protein 3(A20) lung fibrosis lipid nanoparticles mRNA

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