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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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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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Subsequent strategies and underlying mechanism of acquired resistance to PD-1 axis inhibitors in advanced non-small cell lung cancer

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Chinese Medical Journal 2024年第7期137卷 880-882页

作者： Huilan Wang Xinyu Cheng Fan Yang Lu Chen Anmei Zhang Liangzhi Zhong Haixia Long Bo Zhu Zhongyu Wang institute of Cancer Xinqiao HospitalThird Military Medical UniversityChongqing 400037China Chongqing Key Laboratory of immunotherapy Chongqing 400037China

To the Editor:With the widespread application of immune checkpoint inhibitors(ICIs)in clinical practice,acquired resistance(AR)to programmed death-1(PD-1)/programmed death ligand 1(PD-L1)axis inhibitors in advanced nonsmall cell lung cancer(NSCLC)develops and limits the durability of *** is a clinical condition in which a patient initially responds to ICIs but relapses and progresses after a period of *** rates of AR have not been routinely reported in lung cancer but typically range from 12.9%to 64%.[1]However,studies on subsequent management strategies and the mechanism of AR to PD-1/PD-L1 axis inhibitors in lung cancer are *** main exploratory strategies are immunotherapy rechallenge and the combination of ICIs with other therapies,including local therapy,chemotherapy,antiangiogenetic treatment,and cytotoxic T lymphocyte antigen 4(CTLA-4)inhibitors.[2]The purpose of this study was to characterize the clinical patterns of AR and compare different subsequent therapies and outcomes in NSCLC patients after AR to PD-1/PD-L1 ***,we explored the underlying mechanism of AR by analyzing the alterations in next-generation sequencing(NGS)data before and after AR.

关键词： routine alterations resistance

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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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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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The RNA m^(6)A demethylase ALKBH5 drives emergency granulopoiesis and neutrophil mobilization by upregulating G-CSFR expression

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Cellular & Molecular Immunology 2024年第1期21卷 6-18页

作者： Yang Liu Renjie Song Zhike Lu Lu Zhao Xinyi Zhan Yini Li Xuetao Cao Department of Immunology Center for ImmunotherapyInstitute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingChina Suzhou institute of Systems Medicine Chinese Academy of Medical SciencesSuzhouChina Frontier Research Center for Cell Response Institute of ImmunologyCollege of Life SciencesNankai UniversityTianjinChina School of Life Sciences Westlake UniversityHangzhouChina

Emergency granulopoiesis and neutrophil mobilization that can be triggered by granulocyte colony-stimulating factor(G-CSF)through its receptor G-CSFR are essential for antibacterial innate ***,the epigenetic modifiers crucial for intrinsically regulating G-CSFR expression and the antibacterial response of neutrophils remain largely unclear.N6-methyladenosine(m^(6)A)RNA modification and the related demethylase alkB homolog 5(ALKBH5)are key epigenetic regulators of immunity and inflammation,but their roles in neutrophil production and mobilization are still *** used cecal ligation and puncture(CLP)-induced polymicrobial sepsis to model systemic bacterial infection,and we report that ALKBH5 is required for emergency granulopoiesis and neutrophil ***5 depletion significantly impaired the production of immature neutrophils in the bone marrow of septic *** addition,Alkbh5-deficient septic mice exhibited higher retention of mature neutrophils in the bone marrow and defective neutrophil release into the circulation,which led to fewer neutrophils at the infection site than in their wild-type *** bacterial infection,ALKBH5 imprinted production-and mobilization-promoting transcriptome signatures in both mouse and human ***,ALKBH5 erased m^(6)A methylation on the CSF3R mRNA to increase the mRNA stability and protein expression of G-CSFR,consequently upregulating cell surface G-CSFR expression and downstream STAT3 signaling in *** RIP-qPCR results confirmed the direct binding of ALKBH5 to the CSF3R mRNA,and the binding strength declined upon bacterial infection,accounting for the decrease in G-CSFR expression on bacteria-infected *** these results collectively,we define a new role of ALKBH5 in intrinsically driving neutrophil production and mobilization through m^(6)A demethylation-dependent posttranscriptional regulation,indicating that m^(6)A RNA modification in neutrop

关键词： Emergency granulopoiesis Neutrophil mobilization ALKBH5 m^(6)A RNA modification G-CSF receptor

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Revolutionizing tumor immunotherapy:unleashing the power of progenitor exhausted T cells

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Cancer Biology & Medicine 2024年第6期21卷 499-512页

作者： Zhang Fang Xinyi Ding Hao Huang Hongwei Jiang Jingting Jiang Xiao Zheng Department of Tumor Biological Treatment The Third Affiliated Hospital of Soochow UniversityChangzhou 213003China Jiangsu Engineering Research Center for Tumor immunotherapy The Third Affiliated Hospital of Soochow UniversityChangzhou 213003China institute for Cell Therapy of Soochow University The Third Affiliated Hospital of Soochow UniversityChangzhou 213003China

In exploring persistent infections and malignancies, a distinctive subgroup of CD8^(+) T cells, progenitor exhausted CD8^(+) T(Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8^(+) T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.

关键词： Progenitor exhausted CD8^(+)T cells TCF-1 immunotherapy tumor microenvironment cellular crosstalk

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eUREkA! T cells answer nature’s call

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Cellular & Molecular Immunology 2023年第7期20卷 692-693页

作者： Beth Kelly Erika L.Pearce bloomberg-kimmel institute of immunotherapy Department of OncologyJohns Hopkins University School of MedicineBaltimoreMDUSA

Nitrogen is critical for cell growth, proliferation, and function. Amino acid (AA) catabolism is a major source of intracellular nitrogen for biosynthesis but also generates the nitrogen-containing molecule ammonia (NH3+), which can accumulate to toxic levels in a cell if not exported to the circulation and detoxified by the urea cycle in the liver. In a recent paper in Nature Immunology, Tang et al. [1] discovered a functional urea cycle in memory T cells, which metabolizes ammonia, prevents its toxic accumulation.

关键词： function. ammonia cycle

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