The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth

Cancer Cell, Год журнала: 2023, Номер 41(3), С. 374 - 403

Опубликована: Март 1, 2023

Язык: Английский

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Diversity and Biology of Cancer-Associated Fibroblasts

Physiological Reviews, Год журнала: 2020, Номер 101(1), С. 147 - 176

Опубликована: Май 29, 2020

Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite presence of non-neoplastic stromal components that substantially contribute progression tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by surrounding tumor microenvironment (TME). Within TME, cancer-associated fibroblasts (CAFs) been shown play several roles in development a They secrete growth factors, inflammatory ligands, extracellular matrix proteins promote proliferation, therapy resistance, immune exclusion. However, recent work indicates CAFs may also restrain some circumstances. In this review, we summarize body CAFs, with particular focus most discoveries about fibroblast heterogeneity, plasticity, functions. We highlight commonalities present across different types, normal states. Finally, latest advances regarding therapeutic strategies undergoing preclinical clinical evaluation.

Язык: Английский

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Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance

Cancer Cell, Год журнала: 2020, Номер 37(4), С. 471 - 484

Опубликована: Апрель 1, 2020

Язык: Английский

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The matrix in cancer

Nature reviews. Cancer, Год журнала: 2021, Номер 21(4), С. 217 - 238

Опубликована: Фев. 15, 2021

Язык: Английский

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Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Фев. 17, 2023

Abstract Having a hypoxic microenvironment is common and salient feature of most solid tumors. Hypoxia has profound effect on the biological behavior malignant phenotype cancer cells, mediates effects chemotherapy, radiotherapy, immunotherapy through complex mechanisms, closely associated with poor prognosis in various patients. Accumulating studies have demonstrated that normalization tumor vasculature, nanoparticle carriers biocarriers can effectively increase oxygen concentration microenvironment, improve drug delivery efficacy radiotherapy. They also infiltration innate adaptive anti-tumor immune cells to enhance immunotherapy. Furthermore, drugs targeting key genes hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, hypoxia-inducible factors downstream targets, be used for visualization quantitative analysis antitumor activity. However, relationship between an area research requires further exploration. Here, we investigated potential development cancer, changes signaling pathways occur adapt environments, mechanisms hypoxia-induced tolerance, chemotherapeutic enhanced radiation as well insights applications therapy.

Язык: Английский

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Metastasis

Cell, Год журнала: 2023, Номер 186(8), С. 1564 - 1579

Опубликована: Апрель 1, 2023

Язык: Английский

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Immunosenescence: a key player in cancer development

Journal of Hematology & Oncology, Год журнала: 2020, Номер 13(1)

Опубликована: Ноя. 10, 2020

Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling lymphoid organs, leading to changes in the function elderly, which closely related development infections, autoimmune diseases, malignant tumors. T cell-output decline an important feature immunosenescence as well production senescence-associated secretory phenotype, increased glycolysis, reactive oxygen species. Senescent cells exhibit abnormal phenotypes, including downregulation CD27, CD28, upregulation CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, cytotoxic T-lymphocyte-associated protein 4, are tightly The role tumors sophisticated: many factors involved include cAMP, glucose competition, oncogenic stress tumor microenvironment, can induce senescence cells, macrophages, natural dendritic cells. Accordingly, these senescent could also affect progression. In addition, effect on response checkpoint blocking antibody therapy so far ambiguous due low participation elderly cancer patients clinical trials. Furthermore, other senescence-related interventions be possible genetic pharmacological methods, mTOR inhibition, interleukin-7 recombination, NAD+ activation. Overall, this review aims highlight characteristics its impact immunotherapy, especially future directions treatment through senescence-focused strategies.

Язык: Английский

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Immunosenescence: molecular mechanisms and diseases

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Май 13, 2023

Abstract Infection susceptibility, poor vaccination efficacy, age-related disease onset, and neoplasms are linked to innate adaptive immune dysfunction that accompanies aging (known as immunosenescence). During aging, organisms tend develop a characteristic inflammatory state expresses high levels of pro-inflammatory markers, termed inflammaging. This chronic inflammation is typical phenomenon immunosenescence it considered the major risk factor for diseases. Thymic involution, naïve/memory cell ratio imbalance, dysregulated metabolism, epigenetic alterations striking features immunosenescence. Disturbed T-cell pools antigen stimulation mediate premature senescence cells, senescent cells proinflammatory senescence-associated secretory phenotype exacerbates Although underlying molecular mechanisms remain be addressed, well documented T inflammaging might driving forces in Potential counteractive measures will discussed, including intervention cellular metabolic-epigenetic axes mitigate In recent years, has attracted increasing attention its role tumor development. As result limited participation elderly patients, impact on cancer immunotherapy unclear. Despite some surprising results from clinical trials drugs, necessary investigate other

Язык: Английский

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CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

Molecular Therapy, Год журнала: 2020, Номер 28(11), С. 2320 - 2339

Опубликована: Сен. 16, 2020

Chimeric antigen receptor (CAR) T cell therapy has garnered significant excitement due to its success for hematological malignancies in clinical studies leading the US Food and Drug Administration (FDA) approval of three CD19-targeted CAR products. In contrast, experience with solid tumors brain been less encouraging, only a few patients achieving complete responses. Clinical preclinical have identified multiple "roadblocks," including (1) limited array targetable antigens heterogeneous expression, (2) fitness survival before reaching tumor sites, (3) an inability cells efficiently traffic sites penetrate physical barriers, (4) immunosuppressive microenvironment. Herein, we review these challenges discuss strategies that investigators taken improve effector function adoptive immunotherapy tumors. Adoptive therapies utilizing expressing chimeric receptors (CARs) propelled forefront experimental their targeting range antigens, CD19, CD22, CD30, kappa, B maturation (BCMA).1Porter D.L. Levine B.L. Kalos M. Bagg A. June C.H. receptor-modified chronic lymphoid leukemia.N. Engl. J. Med. 2011; 365: 725-733Crossref PubMed Scopus (2158) Google Scholar, 2Grupp S.A. Barrett D. Aplenc R. Porter Rheingold S.R. Teachey D.T. Chew Hauck B. Wright J.F. et al.Chimeric acute 2013; 368: 1509-1518Crossref (1949) 3Maude S.L. Frey N. Shaw P.A. D.M. Bunin N.J. Gonzalez V.E. Zheng Z. Lacey S.F. sustained remissions 2014; 371: 1507-1517Crossref (2496) 4Fry T.J. Shah N.N. Orentas R.J. Stetler-Stevenson Yuan C.M. Ramakrishna S. Wolters P. Martin Delbrook C. Yates al.CD22-targeted induce remission B-ALL is naive or resistant immunotherapy.Nat. 2018; 24: 20-28Crossref (399) 5Gardner R.A. Finney O. Annesley Brakke H. Summers Leger K. Bleakley Brown Mgebroff Kelly-Spratt K.S. al.Intent-to-treat leukemia by CD19 defined formulation dose children young adults.Blood. 2017; 129: 3322-3331Crossref (11) 6Ramos C.A. Grover N.S. Beaven A.W. Lulla P.D. Wu M.F. Ivanova Wang T. Shea T.C. Rooney Dittus al.Anti-CD30 CAR-T relapsed refractory Hodgkin lymphoma.J. Clin. Oncol. 2020; (Published online July 23, 2020. 10.1200/JCO.20.01342)Crossref 7Ramos Savoldo Torrano V. Ballard Zhang Dakhova Liu E. Carrum G. Kamble R.T. Gee A.P. al.Clinical responses lymphocytes malignancy-associated κ light chains.J. Invest. 2016; 126: 2588-2596Crossref (134) 8Raje Berdeja Lin Y. Siegel Jagannath Madduri Liedtke Rosenblatt Maus M.V. Turka al.Anti-BCMA T-cell bb2121 myeloma.N. 2019; 380: 1726-1737Crossref (249) 9Turtle C.J. Hanafi L.A. Berger Hudecek Pender Robinson Hawkins Chaney Cherian Chen X. al.Immunotherapy non-Hodgkin's lymphoma ratio CD8+ CD4+ CD19-specific cells.Sci. Transl. 8: 355ra116Crossref (421) 10Kochenderfer J.N. Somerville R.P.T. Lu Yang J.C. Sherry R.M. Feldman McIntyre L. Bot Rossi Lam Rosenberg Long-duration diffuse large after anti-CD19 therapy.Mol. Ther. 25: 2245-2253Abstract Full Text PDF (114) Scholar The landscape malignancies, successes challenges, subject recent reviews.11Holstein Lunning M.A. hematologic malignancies: voyage progress.Clin. Pharmacol. 107: 112-122Crossref (0) 12Boyiadzis M.M. Dhodapkar Brentjens Kochenderfer Neelapu S.S. Maloney D.G. Grupp Mackall C.L. treatment perspective significance.J. Immunother. Cancer. 6: 137Crossref (48) 13Majzner R.G. lessons learned from first leg journey.Nat. 1341-1355Crossref (58) We therefore do not detail, except highlighting "lessons learned" as they relate tumors, First, can eradicate chemorefractory cancer regardless underlying oncogenic driver mutations; second, lymphodepleting chemotherapy at present sine qua non enable expansion persistence infused cells; third, inclusion least one co-stimulatory signaling domain critical success; fourth: loss variants emerged mechanism therapeutic failure, even are highly homogeneously expressed such CD19; fifth, side effects, cytokine release syndrome (CRS) neurotoxicity.11Holstein 14Neelapu Tummala Kebriaei Wierda W. Locke F.L. Jain Daver Gulbis A.M. Adkins al.Toxicity management therapy: size does fit "ALL".Nat. Rev. 15: 218Crossref 15Lee D.W. Santomasso B.D. Ghobadi Turtle Brudno Park J.H. Mead Pavletic al.ASTCT consensus grading neurologic toxicity associated immune cells.Biol. Blood Marrow Transplant. 625-638Abstract (307) contrast shown antitumor activity early phase testing despite variety target types.16Goff Morgan Robbins P.F. Restifo N.P. Y.C. al.Pilot trial transfer receptor-transduced EGFRvIII glioblastoma.J. 42: 126-135Crossref 17O'Rourke Nasrallah M.P. Desai Melenhorst J.J. Mansfield Morrissette J.J.D. Martinez-Lage Brem Shen al.A single peripherally EGFRvIII-directed mediates induces adaptive resistance recurrent glioblastoma.Sci. 9 (eaaa0984)PubMed 18Morgan Kitano Dudley M.E. Laurencot Case report serious adverse event following administration transduced recognizing ERBB2.Mol. 2010; 18: 843-851Abstract (1312) 19Lamers Sleijfer Vulto A.G. Kruit W.H. Kliffen Debets Gratama J.W. Stoter Oosterwijk Treatment metastatic renal carcinoma autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: experience.J. 2006; e20-e22Crossref (597) 20Lamers van Steenbergen Elzakker Krimpen Groot den Bakker CAIX CAR-engineered cells: evaluation on-target toxicity.Mol. 21: 904-912Abstract (359) 21Kershaw M.H. Westwood J.A. Parker L.L. Eshhar Mavroukakis White D.E. Wunderlich J.R. Canevari Rogers-Freezer I study on using gene-modified ovarian cancer.Clin. Cancer Res. 12: 6106-6115Crossref (733) 22Brown C.E. Alizadeh Starr Weng Wagner Naranjo Ostberg Blanchard M.S. Kilpatrick Simpson al.Regression glioblastoma therapy.N. 375: 2561-2569Crossref 23Ahmed Brawley V.S. Hegde Robertson Ghazi Gerken Ashoori Corder al.Human epidermal growth factor 2 (HER2)-specific HER2-positive sarcoma.J. 2015; 33: 1688-1696Crossref (444) 24Wang Tong Dai Guo Huang Lv Luo al.CD133-directed advanced metastasis trial.OncoImmunology. 7: e1440169Crossref (60) 25Thistlethwaite F.C. Gilham Guest R.D. Rothwell Pillai Burt D.J. Byatte A.J. Kirillova Valle Sharma S.K. al.The efficacy first-generation carcinoembryonic (CEACAM5)-specific poor transient pre-conditioning-dependent respiratory toxicity.Cancer Immunol. 66: 1425-1436Crossref (94) 26Ahmed Bielamowicz Kalra Landi Gray T.L. Diouf Wakefield al.HER2-specific virus-specific progressive glioblastoma: 1 dose-escalation trial.JAMA 3: 1094-1101Crossref (187) This failure most likely multifactorial includes design generation, expression (aka "antigen dilemma"), fitness, inefficient homing penetration (5) hostile microenvironment (TME) (Figure 1).27Rafiq Hackett C.S. Engineering overcome current roadblocks therapy.Nat. 17: 147-167Crossref (46) 28Rodriguez-Garcia Palazon Noguera-Ortega Powell Jr., Guedan hit microenvironment: escape.Front. 11: 1109Crossref 29Schmidts Making option tumors.Front. 9: 2593Crossref 30Knochelmann H.M. Smith A.S. Dwyer Wyatt Mehrotra Paulos tumors: blueprints building effective therapies.Front. 1740Crossref design, genetic approaches aforementioned roadblocks. Since allogeneic mainly explored studies, refer interested reader recently published reviews.31Depil Duchateau Mufti Poirot "Off-the-shelf" development challenges.Nat. Discov. 19: 185-199Crossref (47) Scholar,32Qasim Allogeneic leukemia.Am. Hematol. 94: S50-S54Crossref (10) also CRS neurotoxicity since several reviews covered this topic.14Neelapu Scholar,33Frey Cytokine therapy.Biol. e123-e127Abstract CARs modular consists antigen-binding domain, commonly single-chain variable fragment (scFv) derived monoclonal antibody (mAb), hinge transmembrane intracellular domain.27Rafiq Scholar,34Kuwana Asakura Utsunomiya Nakanishi Arata Itoh Nagase F. Kurosawa Expression composed immunoglobulin-derived V regions receptor-derived C regions.Biochem. Biophys. Commun. 1987; 149: 960-968Crossref (148) 35Gross Waks immunoglobulin-T-cell molecules functional antibody-type specificity.Proc. Natl. Acad. Sci. USA. 1989; 86: 10024-10028Crossref (724) 36Eshhar Gross Schindler Specific activation cytotoxic through chains consisting antibody-binding domains gamma zeta subunits immunoglobulin receptors.Proc. 1993; 90: 720-724Crossref (816) 37June Sadelain 379: 64-73Crossref (436) 38Dotti Gottschalk Brenner M.K. Design receptor-expressing cells.Immunol. 257: 107-126Crossref (256) addition scFvs, natural ligands cytokines peptides bind surface being domains.22Brown Scholar,39Shaffer D.R. Yi Chow K.K. Kakarla Spencer Dotti Kenney redirected CD70 CD70-positive malignancies.Blood. 117: 4304-4314Crossref Scholar,40Davies Foster Van Der Stegen S.J. Parente-Pereira A.C. Chiapero-Stanke Delinassios G.J. Burbridge S.E. Kao Bosshard-Carter al.Flexible ErbB dimers drive tumorigenesis engineered cells.Mol. 2012; 565-576Crossref (54) While recognize epitopes proteins major histocompatibility complex (MHC)-independent manner, scFvs incorporated into peptide context human leukocyte (HLA) molecule.41Ma Q. Garber H.R. He Tallis Ding Sergeeva Wood Salvado novel TCR-like specificity PR1/HLA-A2 effectively targets myeloid vitro when adult peripheral blood cord cells.Cytotherapy. 985-994Abstract 42Rafiq Purdon Daniyan A.F. Koneru Dao Scheinberg D.A. Optimized receptor-mimic directed toward Wilms antigen.Leukemia. 31: 1788-1797Crossref 43Maus Plotkin Jakka Stewart-Jones Rivière I. Merghoub Wolchok Renner An MHC-restricted antibody-based requires affinity maintain specificity.Mol. Oncolytics. 1-9PubMed approach allows molecules, it renders recognition dependent particular HLA type, restricting application subset patients. addition, become sensitive decreased defects processing pathway, both pathways used actively evade responses.44Töpfer Kempe Müller Schmitz Bachmann Cartellieri Schackert Temme Tumor evasion surveillance.J. Biomed. Biotechnol. 2011: 918471Crossref First-generation contained utilized CD3ζ.37June Scholar,38Dotti optimal relies co-stimulation, were included CARs. Initial focused canonical CD28 41BB.37June then, broad explored, OX40, CD27, ICOS.37June Scholar,45Rafiq Yeku O.O. Jackson H.J. Leeuwen Drakes Song Miele Li al.Targeted delivery PD-1-blocking scFv enhances anti-tumor vivo.Nat. 36: 847-856Crossref (161) 46Hombach A.A. Abken Costimulation revisited response benefits combined CD28-OX40 signalling.Int. 2935-2944Crossref (93) 47Collinson-Pautz M.R. Chang W.C. Khalil Crisostomo P.Y. Mahendravada Shinners Brandt al.Constitutively active MyD88/CD40 costimulation malignancies.Leukemia. 2195-2207Crossref (14) 48Guedan Madar Carpenito McGettigan Frigault M.J. Lee Posey A.D. Scholler al.ICOS-based program bipolar TH17/TH1 cells.Blood. 124: 1070-1080Crossref (162) 49Nair J.B. Tsao S.T. Zhu Slayton W.B. Moreb J.S. Dong L.J. Functional improvement intrinsic interleukin-15Rα signaling.Curr. Gene 40-53Crossref (7) 41BB co-stimulation extensively studied, detailed phosphoproteomic single-cell RNA sequencing (RNA-seq) analyses.50Salter A.I. Ivey Kennedy Voillet Rajan Alderman E.J. Voytovich U.J. Sommermeyer al.Phosphoproteomic analysis reveals kinetic quantitative differences affect function.Sci. Signal. eaat6753Crossref 51Boroughs Larson R.C. Marjanovic N.D. Gosik Castano C.B.M. Lorrey Ashenberg Jerby Hofree distinct transcriptional bearing 4-1BB revealed scRNA-seq.Mol. 25, 2020)https://doi.org/10.1016/j.ymthe.2020.07.023Abstract 52Xhangolli Dura Kim Xiao Fan Single-cell mixed TH1/TH2 independent differentiation.Genomics Proteomics Bioinformatics. 129-139Crossref (13) They activate different within cells, promoting glycolytic metabolism memory phenotype, signaling, which oxidative central phenotype.53Kawalekar O.U. O' Connor R.S. Fraietta Patel P.R. Keith al.Distinct coreceptors regulates specific impacts cells.Immunity. 44: 712Abstract (36) Depending number either designated second (one domain) third (two domains) generation. benefit two model-dependent.54Quintarelli Orlando Boffa Guercio Polito V.A. Petretto Lavarello Sinibaldi Weber Del Bufalo al.Choice costimulatory determines neuroblastoma.OncoImmunology. e1433518Crossref (37) Scholar,55Zhao Condomines der S.J.C. Perna Kloss C.C. Gunset Structural rejection kinetics cells.Cancer Cell. 28: 415-428Abstract (288) Results study, comparing CD28-CAR versus CD28.41BB-CAR suggest third-generation endow greater ability expand infusion humans.56Ramos Rouce Reyna Narala Vyas Mehta al.In vivo fate second- lymphomas.Mol. 26: 2727-2737Abstract (52) Optimizing remains challenge there intricate interplay between (antigen nonfunctional components (hinge CARs.57Guest R.E. Cheadle Arnold O'Neill Irlam Chester K.A. Kemshead J.T. role extracellular spacer receptors: four antigens.J. 2005; 203-211Crossref Scholar,58Majzner Rietberg S.P. Sotillo Vachharajani V.T. Labanieh Myklebust Kadapakkam E.W. Tousley al.Tuning density requirement activity.Cancer 10: 702-723Crossref (17) location epitope targeted molecule activity.59Hudecek Lupo-Stanghellini M.T. Kosasih P.L. Jensen M.C. Rader Riddell Receptor modifications ROR1-specific cells.Clin. 3153-3164Crossref (246) For example, proximal plasma membrane than distal epitopes.57Guest Scholar,59Hudecek Scholar,60James Greenberg Till B.G. Raubitschek Forman Press O.W. Antigen sensitivity CD22-specific TCR modulated distance membrane.J. 2008; 180: 7028-7038Crossref (126) Studies highlighted too much detrimental function. mutated immunoreceptor tyrosine-based motifs (ITAMs) CD3ζ chain improved function.61Feucht Sun Eyquem Ho Y.J. Zhao Leibold Dobrin Cabriolu Hamieh Calibration potential directs alternative fates potency.Nat. 82-88Crossref (81) excessive effects,62Wijewarnasuriya Bebernitz Lopez A.V. Rafiq Excessive leads dysfunction adoptively transferred 732-742Crossref mutations YMXM motif reduce function.63Guedan Casado-Medrano Wing Young Single residue CD28-costimulated limits long-term durability.J. 130: 3087-3097Crossref (12) activation, baseline tonic) activity.64Long A.H. Haso W.M. Shern Wanhainen K.M. Murgai Ingaramo J.P. Walker Kohler Venkateshwara V.R. al.4-1BB ameliorates exhaustion induced tonic receptors.Nat. 581-590Crossref (528) Scholar,65Gomes-Silva Mukherjee Srinivasan Krenciute Cabral J.M.S. Orange Mamonkin Tonic impedes vector-dependent.Cell Rep. 17-26Abstract (80) Recently, studying immunological synapse formed correlated formation effectiveness.66Xiong Kang Hsu Y.H. Jang Qin Immunological predicts effectiveness 963-975Abstract (35) Scholar,67Davenport Cross Watson Liao Shi Prince Beavis Trapani Kershaw Ritchie D.S. form nonclassical potent synapses driving rapid cytotoxicity.Proc. 115: E2068-E2076Crossref (69) Lastly, limit

Язык: Английский

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Tumor‐Microenvironment‐Responsive Nanomedicine for Enhanced Cancer Immunotherapy

Advanced Science, Год журнала: 2021, Номер 9(1)

Опубликована: Ноя. 19, 2021

Abstract The past decades have witnessed great progress in cancer immunotherapy, which has profoundly revolutionized oncology, whereas low patient response rates and potential immune‐related adverse events remain major clinical challenges. With the advantages of controlled delivery modular flexibility, nanomedicine offered opportunities to strengthen antitumor immune responses sensitize tumor immunotherapy. Furthermore, tumor‐microenvironment (TME)‐responsive been demonstrated achieve specific localized amplification tissue a safe effective manner, increasing immunotherapy reducing side effects simultaneously. Here, recent TME‐responsive for is summarized, responds signals TME, such as weak acidity, reductive environment, high‐level reactive oxygen species, hypoxia, overexpressed enzymes, adenosine triphosphate. Moreover, combine nanomedicine‐based therapy immunotherapeutic strategies overcome each step cancer‐immunity cycle enhance discussed. Finally, existing challenges further perspectives this rising field with hope improved development applications are

Язык: Английский

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