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cancer-cell-intrinsic mechanisms shaping the immunosuppressive landscape of prostate cancer

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Asian Journal of Andrology 2023年第2期25卷 171-178页

作者： Yini Zhu Loan Duong Xuemin Lu Xin Lu Department of Biological Sciences Boler-Parseghian Center for Rare and Neglected DiseasesHarper Cancer Research InstituteUniversity of Notre DameNotre DameIN 46556USA Integrated Biomedical Sciences Graduate Program University of Notre DameNotre DameIN 46556USA Tumor Microenvironment and Metastasis Program Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolisIN 46202USA

Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical *** particular,advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade *** is primarily due to the immunosuppressive tumor microenvironment of prostate ***,it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive ***,we review recent findings that reveal the roles of the genetic alterations,androgen receptor signaling,cancer cell plasticity,and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy *** on preclinical and clinical observations,a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.

关键词： immune checkpoint blockade immunosuppression immunotherapy neuroendocrine prostate cancer prostate cancer

N^6-Methyladenosine modification: a novel pharmacological target for anti-cancer drug development

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Acta Pharmaceutica Sinica B 2018年第6期8卷 833-843页

作者： Yi Niu Arabella Wan Ziyou Lin Xiongbin Lu Guohui Wan School of Pharmaceutical Sciences Sun Yat-Sen University School of Medical Laboratory Science Pennsylvania Hospital Department of Medical and Molecular Genetics Indiana University School of Medicine Indiana University melvin and bren simon cancer center

N6-Methyladenosine(m6 A) modification is the most pervasive modification of human mRNA molecules. It is reversible via regulation of m6 A modification methyltransferase, demethylase and proteins that preferentially recognize m6 A modification as "writers", "erasers" and "readers", respectively. Altered expression levels of the m6 A modification key regulators substantially affect their function, leading to significant phenotype changes in the cell and organism. Recent studies have proved that the m6 A modification plays significant roles in regulation of metabolism, stem cell self-renewal, and metastasis in a variety of human cancers. In this review, we describe the potential roles of m6 A modification in human cancers and summarize their underlying molecular mechanisms. Moreover, we will highlight potential therapeutic approaches by targeting the key m6 A modification regulators for cancer drug development.& 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://***/licenses/by-nc-nd/4.0/).

关键词： N^6-Methyladenosine Human cancer Pharmacological target m^6A modification regulator Drug development

CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

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Cellular & Molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand P.Sharda Mackenzie M.Lieberman Caitlin M.James Shivana M.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou Andrew M.Intlekofer Richard M.Higashi Teresa W.M.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of Medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Present address:University of Colorado Boulder BoulderCO 80309USA Present address:Dana Farber cancer Institute BostonMA 02215USA Present address:Massachusetts Institute of Technology BostonMA 02139USA Present address:melvin and bren simon comprehensive cancer center Indiana University School of MedicineIndianapolisIN 46202USA

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been *** this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T *** doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose ***2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing *** these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector ***,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKM2

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

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World Journal of Gastroenterology 2024年第13期30卷 1815-1835页

作者： Samantha Sharma Naresh Singh Anita Ahmed Turk Isabella Wan Akshay Guttikonda Julia Lily Dong Xinna Zhang Mateusz Opyrchal Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN 46202United States Division of Hematology/Oncology Department of MedicineIndiana University School of MedicineIndianapolisIN 46202United States melvin and bren simon comprehensive cancer center Indiana University School of MedicineIndianapolisIN 46202United States

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical *** considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely *** the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint *** aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor *** therapies thus have shown promising results in many clinical trials alone or in *** efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical *** trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair ***,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC *** this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the *** review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in *** underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

关键词： Colorectal cancer Immune checkpoint inhibitors Clinical trials Immunotherapy Microsatellite instability Microsatellite stability DNA mismatch repair

Drug resistance and new therapies in colorectal cancer

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World Journal of Gastroenterology 2018年第34期24卷 3834-3848页

作者： Kevin Van der Jeught Han-Chen Xu Yu-Jing Li Xiong-Bin Lu Guang Ji Institute of Digestive Diseases Longhua HospitalShanghai University of Traditional Chinese Medicine Department of Medical and Molecular Genetics Indiana University School of Medicine Indiana University melvin and bren simon cancer center Indiana University School of Medicine

Colorectal cancer(CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo-and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo-and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibodydrug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.

关键词： Colorectal cancer Therapy resistance Antibody-drug conjugates α-amanitin Tumor microenvironment Immunotherapy Checkpoint inhibitors Microbiome

Targeting and exploitation of tumor-associated neutrophils to enhance immunotherapy and drug delivery for cancer treatment

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cancer Biology & Medicine 2020年第1期17卷 32-43页

作者： Yuting Zhang Guoqiang Liu Miaomiao Sun Xin Lu Department of Biological Sciences Boler-Parseghian Center for Rare and Neglected DiseasesHarper Cancer Research InstituteUniversity of Notre DameNotre DameIN 46556USA Integrated Biomedical Sciences Graduate Program University of Notre DameNotre DameIN 46556USA Tumor Microenvironment and Metastasis Program Indiana University Melvin and Bren Simon Cancer CenterIndianapolisIN 46202USA

Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial *** on the finding that neutrophils can either restrict or promote cancer progression,tumor-associated neutrophils(TAN)are classified into anti-tumor N1 and pro-tumor N2 *** of the major mechanisms underlying the tumor-promoting function of N2-TANs is suppression of adaptive immune cells,in particular,cytotoxic T ***,no established methodologies are available that can unequivocally distinguish immunosuppressive TANs and granulocytic/polymorphonuclear myeloid-derived suppressor cells(G/PMN-MDSC).In view of the critical role of PMN-MDSCs in immune evasion and resistance to cancer immunotherapy,as established from data obtained with diverse cancer models,therapeutic strategies targeting these cells have been actively developed to enhance the efficacy of ***,we have reviewed the available literature on strategies targeting PMN-MDSCs and summarized the findings into four categories:(1)depletion of existing PMN-MDSCs,(2)blockade of the development of PMNMDSCs,(3)blockade of PMN-MDSC recruitment,(4)inhibition of immunosuppressive *** to their high mobility to inflamed organs and ability to trespass the blood-brain barrier,neutrophils are outstanding candidate carriers in nanoparticle-based *** attractive application of neutrophils in cancer therapy is the use of neutrophil membrane-derived nanovesicles as a surrogate of extracellular vesicles for more efficient and scalable drug *** the second part of the review,we have highlighted recent advances in the field of neutrophil-based cancer drug ***,we believe that neutrophil-based therapeutics are a rapidly growing area of cancer therapy with significant potential benefits.

关键词： Tumor-associated neutrophil polymorphonuclear myeloid-derived suppressor cell immunosuppression cancer immunotherapy nanoparticle drug delivery

Spatial relationship of tertiary lymphoid structures and tumor-associated neutrophils in bladder cancer and prognostic potential for anti-PD-L1 immunotherapy

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cancer Communications 2024年第4期44卷 499-503页

作者： Xuechun Wang Anna Juncker-Jensen Gang Huang Mate Levente Nagy Xuemin Lu Liang Cheng Xin Lu Department of Biological Sciences Boler-Parseghian Center for Rare and Neglected DiseasesHarper Cancer Research InstituteUniversity of Notre DameNotre DameINUSA NeoGenomics Laboratories Inc.Aliso ViejoCAUSA Department of Pathology and Laboratory Medicine Brown University Warren Alpert Medical SchoolLifespan Academic Medical CenterLegorreta Cancer Center at Brown UniversityProvidenceRIUSA Tumor Microenvironment and Metastasis Program Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolisINUSA

Dear Editor,Tertiary lymphoid structures(TLSs)are organized clus-ters of immune cells found in non-lymphoid tissues of chronic inflammation,including solid tumors[1].High endothelial venules(HEVs)positive for peripheral node addressin(PNAd)are present in TLSs and may pro-vide highway entry for ***-residing TLSs may be formed by the concerted actions of cytokines and chemokines,a finding supported by the relation between a 12-chemokine signature and TLSs[2].

关键词： bladder lymphoid inflammation

Sperm hyaluronidase is critical to mammals'fertilization for its ability to disperse cumulus-oocyte complex layer

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Asian Journal of Andrology 2022年第4期24卷 411-415页

作者： Dong-Won Seol Sang Hoon Joo Young-Hyun Kim Bong-Seok Song Bo-Woong Sim Sun-Uk Kim Soojin Park Gabbine Wee Ekyune Kim Laboratory Animal center Daegu-Gyeongbuk Medical Innovation Foundation(DGMIF)Daegu 41061Korea College of Pharmacy Catholic University of DaeguGyeongbuk 38430Korea National Primate Research center(NPCR) Korea Research Institute of Bioscience and BiotechnologyChungcheongbuk-do 28116Korea Futuristic Animal Resource and Research center Korea Research Institute of Bioscience and BiotechnologyChungcheongbuk-do 28116Korea Department of Biochemistry and Molecular Biology Melvin and Bren Simon Comprehensive Cancer CenterIndiana University School of MedicineIndianapolisIN 46202USA

Glycosylphosphatidylinositol-anchored sperm hyaluronidases have long been believed to assist in sperm penetration through the cumulus-oocyte complex(COC);however,their role in mammalian fertilization remains ***,we have shown that hyaluronidase 5(Hyal5)/Hyal7 double-knockout(dKO)mice produce significantly fewer offspring than their wild-type(WT)counterparts because of defective COC *** infertility is mainly caused by a low sperm *** can be further exacerbated by the deficiency of sperm hyaluronidase,which disperses the cumulus cells of the outer layer of the *** the current study,we evaluated the effects of a low count of Hyal-deficient sperm and conditions of ovulated oocytes on the fertilization rate using a mouse *** results demonstrated that a low sperm count further decreases the in vitro fertilization(IVF)rate of Hyal-deficient dKO *** addition,the dKO spermatozoa resulted in a fertilization rate of 12.5%upon fertilizing COCs with a thick cumulus layer,whereas the IVF rate was comparable to that of WT spermatozoa when oocytes with a thin or no cumulus layer were ***,we proved that the IVF rate of dKO spermatozoa could be recovered by adding rat spermatozoa as a source of sperm *** results suggest that a deficiency of proteins involved in fertilization,such as sperm hyal,has a vital role in fertilization.

关键词： HYAL5 HYAL7 cumulus-oocyte complex fertilization infertility sperm hyaluronidase

Distinct transcriptomic landscapes of cutaneous basal cell carcinomas and squamous cell carcinomas

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Genes & Diseases 2021年第2期8卷 181-192页

作者： Jun Wan Hongji Dai Xiaoli Zhang Sheng Liu Yuan Lin Ally-Khan Somani Jingwu Xie Jiali Han Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN46202USA center for Computational Biology and Bioinformatics Indiana University School of MedicineIndianapolisIN46202USA School of Informatics and Computing Indiana University e Purdue University at IndianapolisIndianapolisIN46202USA Department of Epidemiology and Biostatistics Key Laboratory of Cancer Prevention and TherapyNational Clinical Research Center of CancerTianjin Medical University Cancer Institute and HospitalTianjin300000PR China Wells center for Pediatric Research Department of PediatricsIndiana University School of MedicineIndianapolisIN46202USA melvin and bren simon cancer center Indiana University School of MedicineIndianapolisIN46202USA Department of Epidemiology Richard M.Fairbanks School of Public HealthIndiana UniversityIndianapolisIN46202USA Dermatologic Surgery&Cutaneous Oncology Division Department of DermatologyIndiana University School of MedicineIndianapolisIN46202USA

The majority of non-melanoma skin cancer(NMSC)is cutaneous basal cell carcinoma(BCC)or squamous cell carcinoma(SCC),which are also called keratinocyte carcinomas,as both of them originate from *** incidence of keratinocyte carcinomas is over 5 million per year in the US,three-fold higher than the total incidence of all other types of cancer *** there are several reports on gene expression profiling of BCC and SCC,there are significant variations in the reported gene expression changes in different *** reason is that tumor-adjacent normal skin specimens were not included in many studies as matched ***,while numerous studies of skin stem cells in mouse models have been reported,their relevance to human skin cancer remains *** this report,we analyzed gene expression profiles of paired specimens of keratinocyte carcinomas with their matched normal skin tissues as the *** several novel findings,we discovered a significant number of zinc finger encoding genes up-regulated in human *** BCC,a novel link was found between hedgehog signaling,Wnt signaling,and the *** the SCC cancerstem-cell gene signature is shared between human and mouse SCCs,the hair follicle stem-cell signature of mice was not highly represented in human *** gene expression(DEG)in human BCC shares gene signature with both bulge and epidermal stem *** have also determined that human BCCs and SCCs have distinct gene expression patterns,and some of them are not fully reflected in current mouse models.

关键词： Basal cell carcinoma Gli1 Hedgehog signaling PTCH1 Squamous cell carcinoma