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Keresztes D, Kerestély M, Szarka L, Kovács BM, Schulc K, Veres DV, Csermely P. Cancer drug resistance as learning of signaling networks. Biomed Pharmacother 2025; 183:117880. [PMID: 39884030 DOI: 10.1016/j.biopha.2025.117880] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/08/2025] [Accepted: 01/27/2025] [Indexed: 02/01/2025] Open
Abstract
Drug resistance is a major cause of tumor mortality. Signaling networks became useful tools for driving pharmacological interventions against cancer drug resistance. Signaling datasets now cover the entire human cell. Recently, network adaptation became understood as a learning process. We review rapidly increasing evidence showing that the development of cancer drug resistance can be described as learning of signaling networks. During drug adaptation, the network forgets drug-affected pathways by desensitization and relearns by strengthening alternative pathways. Thus, resistant cancer cells develop a drug resistance memory. We show that all key players of cellular learning (i.e., IDPs, protein translocation, microRNAs/lncRNAs, scaffolding proteins and epigenetic/chromatin memory) have important roles in the development of cancer drug resistance. Moreover, all of them are central components of the epithelial-mesenchymal transition leading to metastases and resistance. Phenotypic plasticity was recently listed as a hallmark of cancer. We review how network plasticity induces rare, pre-existent drug-resistant cells in the absence of drug treatment. Key network methods assessing the development of drug resistance and network pharmacological interventions against drug resistance are summarized. Finally, we highlight the class of cellular memory drugs affecting cellular learning and forgetting, and we summarize current challenges to prevent or break drug resistance using network models.
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Affiliation(s)
- Dávid Keresztes
- Department of Molecular Biology, Semmelweis University, Budapest, Hungary
| | - Márk Kerestély
- Department of Molecular Biology, Semmelweis University, Budapest, Hungary
| | - Levente Szarka
- Department of Molecular Biology, Semmelweis University, Budapest, Hungary
| | - Borbála M Kovács
- Department of Molecular Biology, Semmelweis University, Budapest, Hungary
| | - Klára Schulc
- Department of Molecular Biology, Semmelweis University, Budapest, Hungary; Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Dániel V Veres
- Department of Molecular Biology, Semmelweis University, Budapest, Hungary; Turbine Simulated Cell Technologies, Budapest, Hungary
| | - Peter Csermely
- Department of Molecular Biology, Semmelweis University, Budapest, Hungary.
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2
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Glaviano A, Lau HSH, Carter LM, Lee EHC, Lam HY, Okina E, Tan DJJ, Tan W, Ang HL, Carbone D, Yee MYH, Shanmugam MK, Huang XZ, Sethi G, Tan TZ, Lim LHK, Huang RYJ, Ungefroren H, Giovannetti E, Tang DG, Bruno TC, Luo P, Andersen MH, Qian BZ, Ishihara J, Radisky DC, Elias S, Yadav S, Kim M, Robert C, Diana P, Schalper KA, Shi T, Merghoub T, Krebs S, Kusumbe AP, Davids MS, Brown JR, Kumar AP. Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition. J Hematol Oncol 2025; 18:6. [PMID: 39806516 PMCID: PMC11733683 DOI: 10.1186/s13045-024-01634-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 11/11/2024] [Indexed: 01/16/2025] Open
Abstract
The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.
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Affiliation(s)
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Hannah Si-Hui Lau
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Lukas M Carter
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - E Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Donavan Jia Jie Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Wency Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Hui Li Ang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Michelle Yi-Hui Yee
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Xiao Zi Huang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Lina H K Lim
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Ruby Yun-Ju Huang
- School of Medicine and Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
- Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, 23538, Lübeck, Germany
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, UMC, Vrije Universiteit, HV Amsterdam, 1081, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, 56017, San Giuliano, Italy
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
- Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Tullia C Bruno
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy, Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Bin-Zhi Qian
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, The Human Phenome Institute, Zhangjiang-Fudan International Innovation Center, Fudan University, Shanghai, China
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, W12 0BZ, UK
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Salem Elias
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Saurabh Yadav
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Minah Kim
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Caroline Robert
- Department of Cancer Medicine, Inserm U981, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France
- Faculty of Medicine, University Paris-Saclay, Kremlin Bicêtre, Paris, France
| | - Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Kurt A Schalper
- Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Tao Shi
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Taha Merghoub
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Department of Medicine, Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, NY, USA
| | - Simone Krebs
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anjali P Kusumbe
- Tissue and Tumor Microenvironment Group, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Matthew S Davids
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jennifer R Brown
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
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Mattioda C, Voena C, Ciardelli G, Mattu C. In Vitro 3D Models of Haematological Malignancies: Current Trends and the Road Ahead? Cells 2025; 14:38. [PMID: 39791739 PMCID: PMC11720277 DOI: 10.3390/cells14010038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025] Open
Abstract
Haematological malignancies comprise a diverse group of life-threatening systemic diseases, including leukaemia, lymphoma, and multiple myeloma. Currently available therapies, including chemotherapy, immunotherapy, and CAR-T cells, are often associated with important side effects and with the development of drug resistance and, consequently, disease relapse. In the last decades, it was largely demonstrated that the tumor microenvironment significantly affects cancer cell proliferation and tumor response to treatment. The development of biomimetic, in vitro models may promote the investigation of the interactions between cancer cells and the tumor microenvironment and may help to better understand the mechanisms leading to drug resistance. Although advanced in vitro models have been largely explored in the field of solid tumors, due to the complex nature of the blood cancer tumor microenvironment, the mimicking of haematological malignancies mostly relies on simpler systems, often limited to two-dimensional cell culture, which intrinsically excludes the microenvironmental niche, or to ethically debated animal models. This review aims at reporting an updated overview of state-of-the-art hematological malignancies 3D in vitro models, emphasizing the key features and limitations of existing systems to inspire further research in this underexplored field.
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Affiliation(s)
- Carlotta Mattioda
- DIMEAS, Politecnico di Torino, C.so Duca degli Abruzzi 24, 10129 Torino, Italy; (C.M.); (G.C.)
| | - Claudia Voena
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy;
| | - Gianluca Ciardelli
- DIMEAS, Politecnico di Torino, C.so Duca degli Abruzzi 24, 10129 Torino, Italy; (C.M.); (G.C.)
| | - Clara Mattu
- DIMEAS, Politecnico di Torino, C.so Duca degli Abruzzi 24, 10129 Torino, Italy; (C.M.); (G.C.)
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Azoulay D, Tapuchi T, Ronen O, Akria L, Cohen HI, Surio C, Chepa SR, Eshel E, Zarfati M, Stemer G, Horowitz NA. Flow-cytometry Assessment of DNA content and Immunophenotyping of Immune-cells in Lymph-node-specimens as a Potential Diagnostic Signature of Aggressiveness in B-Non-Hodgkin Lymphomas. Ann Hematol 2024; 103:4203-4210. [PMID: 38777843 PMCID: PMC11512821 DOI: 10.1007/s00277-024-05807-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024]
Abstract
Flow-cytometry (FC) is a powerful tool that can assist in lymphoma diagnosis in lymph node (LN) specimens. Although lymphoma diagnosis and classification are mainly based on tumor cell characteristics, surrounding cells are less employed in this process. We retrospectively investigated alterations in the ploidy status, proliferative cell fraction (PF) and the percentages of surrounding immune cells in 62 consecutive LN specimens with B-Cell Non-Hodgkin Lymphoma (B-NHL) that were submitted for FC evaluation between 2019-2022. Compared with indolent B-NHLs, aggressive B-NHLs show increased DNA aneuploidy and PF, increased monocytes, immature-granulocytes, mature granulocytes, CD8+ T-cells, Double-Negative-T-cells and Double-Positive-T-cells, and decreased total CD45+ cells, total lymphocytes, CD4+ T-cells and CD4/CD8 ratio. Receiver operating characteristic analysis determined PF > 6.8% and immature-granulocytes > 0.9% as optimal cutoffs with highest specificity and sensitivity in differentiating aggressive and indolent B-NHLs. These findings further strength the diagnostic value of DNA content analysis by FC and suggest the utilization of tumor surrounding immune cells in NHL diagnosis and classification.
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Affiliation(s)
- David Azoulay
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.
- Hematology Unit and Laboratories, Galilee Medical Center, Nahariya, Israel.
| | - Tal Tapuchi
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
| | - Ohad Ronen
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Department of Otolaryngology - Head and Neck Surgery, Director Head and Neck Surgery Unit, Galilee Medical Center, Nahariya, Israel
| | - Luiza Akria
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Hematology Unit and Laboratories, Galilee Medical Center, Nahariya, Israel
| | - Hector I Cohen
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Pathology Unit and Laboratories, Galilee Medical Center, Nahariya, Israel
| | - Celia Surio
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Hematology Unit and Laboratories, Galilee Medical Center, Nahariya, Israel
| | | | - Elizabeth Eshel
- Hematology Unit and Laboratories, Ziv Medical Center, Safed, Israel
| | - Moran Zarfati
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Hematology Unit and Laboratories, Galilee Medical Center, Nahariya, Israel
| | - Galia Stemer
- Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
- Hematology Unit and Laboratories, Galilee Medical Center, Nahariya, Israel
| | - Netanel A Horowitz
- The Ruth and Bruce Rappaport Faculty of Medicine, Department of Hematology and BMT, Rambam Health Care Campus, Israel Institute of Technology, Haifa, TechnionHaifa, Israel
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5
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Tang X, Yang ZZ, Kim HJ, Anagnostou T, Yu Y, Wu X, Chen J, Krull JE, Wenzl K, Mondello P, Bhardwaj V, Wang J, Novak AJ, Ansell SM. Phenotype, Function, and Clinical Significance of CD26+ and CD161+Tregs in Splenic Marginal Zone Lymphoma. Clin Cancer Res 2022; 28:4322-4335. [PMID: 35686915 PMCID: PMC10443733 DOI: 10.1158/1078-0432.ccr-22-0977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/17/2022] [Accepted: 06/08/2022] [Indexed: 12/14/2022]
Abstract
PURPOSE Regulatory T-cells (Treg) are essential to Tregs homeostasis and modulate the antitumor immune response in patients with lymphoma. However, the biology and prognostic impact of Tregs in splenic marginal zone lymphoma (SMZL) have not been studied. EXPERIMENTAL DESIGN Biopsy specimens from 24 patients with SMZL and 12 reactive spleens (rSP) from individuals without lymphoma were analyzed by using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), CyTOF (mass cytometry) analysis, and flow cytometry to explore the phenotype, transcriptomic profile, and clinical significance of intratumoral Tregs and their subsets. The biological characteristics and cell signaling pathways of intratumoral Treg subsets were confirmed by in vitro functional assays. RESULTS We found that Tregs are more abundant in SMZL patients' spleens than rSP, and Tregs from patients with SMZL and rSP can be separated into CD161+Treg and CD26+Treg subsets. CD161+Tregs are increased in SMZL but have dysregulated immune function. We found that CD161+Treg and CD26+Tregs have unique gene expression and phenotypic profiles and are differentially correlated with patient outcomes. Specifically, increased CD161+Tregs are significantly associated with a favorable prognosis in patients with SMZL, whereas CD26+Tregs are associated with a poor prognosis. Furthermore, activation of the IL2/STAT5 pathway contributes to the induction of CD26+Tregs and can be reversed by STAT5 inhibition. CONCLUSIONS IL2/STAT5-mediated expansion of CD26+Tregs contributes to a poor clinical outcome in SMZL and may represent a therapeutic opportunity in this disease.
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Affiliation(s)
- Xinyi Tang
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Zhi-Zhang Yang
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Hyo Jin Kim
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Theodora Anagnostou
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Yue Yu
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Xiaosheng Wu
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Jun Chen
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Jordan E. Krull
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Kerstin Wenzl
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Patrizia Mondello
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Vaishali Bhardwaj
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Junwen Wang
- Department of Quantitative Health Sciences and Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona
| | - Anne J. Novak
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Stephen M. Ansell
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
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Denizot Y, Braza MS, Amin R. Editorial: B Cell Non-Hodgkin’s Lymphoma & Tumor Microenvironment Crosstalk: An Epigenetic Matter? Front Genet 2022; 13:912737. [PMID: 35664310 PMCID: PMC9161633 DOI: 10.3389/fgene.2022.912737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 04/07/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Y Denizot
- UMR CNRS 7276, INSERM U1262, Equipe Labellise LIGUE 2018, Universite de Limoges, CBRS, Limoges, France
| | - MS Braza
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - R Amin
- Department of Biochemistry, University of Nebraska at Lincoln, Lincoln, NE, United States
- *Correspondence: R Amin,
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Abstract
The therapeutic armamentarium has significantly expanded since the approval of various CD19-targeting chimeric antigen receptor T cell (CAR-T) therapies in non-Hodgkin lymphoma (NHL). These CAR-Ts are patient-specific and require a complex, resource, and time-consuming process. While this appears promising, autologous CAR-Ts are limited due to the lack of accessibility, manufacturing delays, and variable product quality. To overcome these, allogeneic (allo) CARs from healthy donors appear appealing. These can be immediately available as “off the shelf” ready-to-use products of standardized and superior quality exempt from the effects of an immunosuppressive tumor microenvironment and prior treatments, and potentially with lower healthcare utilization using industrialized scale production. Allogeneic CARs, however, are not devoid of complications and require genomic editing, especially with αβ T cells to avoid graft versus host disease (GvHD) and allo-rejection by the recipient’s immune system. Tools for genomic editing such as TALEN and CRISPR provide promise to develop truly “off the shelf” universal CARs and further advance the field of cellular immunotherapy. Several allogeneic CARs are currently in early phase clinical trials, and preliminary data is encouraging. Longer follow-up is required to truly assess the feasibility and safety of these techniques in the patients. This review focuses on the strategies for developing allogeneic CARs along with cell sources and clinical experience thus far in lymphoma.
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8
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Human CD22-Transgenic, Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments. Int J Mol Sci 2021; 22:ijms221910433. [PMID: 34638774 PMCID: PMC8508822 DOI: 10.3390/ijms221910433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 12/20/2022] Open
Abstract
Targeted immunotherapies have greatly changed treatment of patients with B cell malignancies. To further enhance immunotherapies, research increasingly focuses on the tumor microenvironment (TME), which differs considerably by organ site. However, immunocompetent mouse models of disease to study immunotherapies targeting human molecules within organ-specific TME are surprisingly rare. We developed a myc-driven, primary murine lymphoma model expressing a human-mouse chimeric CD22 (h/mCD22). Stable engraftment of three distinct h/mCD22+ lymphoma was established after subcutaneous and systemic injection. However, only systemic lymphoma showed immune infiltration that reflected human disease. In this model, myeloid cells supported lymphoma growth and showed a phenotype of myeloid-derived suppressor cells. The human CD22-targeted immunotoxin Moxetumomab was highly active against h/mCD22+ lymphoma and similarly reduced infiltration of bone marrow and spleen of all three models up to 90-fold while efficacy against lymphoma in lymph nodes varied substantially, highlighting relevance of organ-specific TME. As in human aggressive lymphoma, anti-PD-L1 as monotherapy was not efficient. However, anti-PD-L1 enhanced efficacy of Moxetumomab suggesting potential for future clinical application. The novel model system of h/mCD22+ lymphoma provides a unique platform to test targeted immunotherapies and may be amenable for other human B cell targets such as CD19 and CD20.
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Ennishi D. The biology of the tumor microenvironment in DLBCL: Targeting the "don't eat me" signal. J Clin Exp Hematop 2021; 61:210-215. [PMID: 34511583 PMCID: PMC8808113 DOI: 10.3960/jslrt.21015] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma with biologically and clinically heterogeneous features. Recently, the tumor microenvironment of this disease has been recognized as an important biological aspect of tumor development and therapeutic targets. Recurrent genetic alterations play significant roles in immune recognition of lymphoma cells. In particular, novel genetic alterations promoting phagocytosis were identified, suggesting a potential therapeutic strategy targeting the “don’t eat me” signal.
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Affiliation(s)
- Daisuke Ennishi
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
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10
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Popovic LS, Matovina-Brko G, Popovic M, Popovic M, Cvetanovic A, Nikolic I, Kukic B, Petrovic D. Immunotherapy in the treatment of lymphoma. World J Stem Cells 2021; 13:503-520. [PMID: 34249225 PMCID: PMC8246244 DOI: 10.4252/wjsc.v13.i6.503] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/31/2021] [Accepted: 05/08/2021] [Indexed: 02/06/2023] Open
Abstract
Relapsed or refractory non-Hodgkin’s lymphomas, especially diffuse large B-cell lymphoma as well as relapsed or refractory Hodgkin lymphomas are hard-to-treat diseases. Patients who do not respond to initial therapy or experience relapse are treated with salvage regimens, and if eligible for aggressive therapy, treatment is continued with high-dose chemotherapy and autologous stem cell transplantation. Current therapy options can cure substantial numbers of patients, however for some it is still an uncurable disease. Numerous new drugs and cell therapies are being investigated for the treatment of relapsed or refractory lymphomas. Different types of immunotherapy options have shown promising results, and some have already become the standard of care. Here, we review immunotherapy options for the treatment of lymphoma and discuss the results, positions, practical aspects, and future directions of different drugs and cellular therapies for the treatment of this disease.
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Affiliation(s)
- Lazar S Popovic
- Department for Medical Oncology, Oncology Institute of Vojvodina, University of Novi Sad, Novi Sad 21000, Serbia
| | - Gorana Matovina-Brko
- Department for Medical Oncology, Oncology Institute of Vojvodina, Novi Sad 21000, Serbia
| | - Maja Popovic
- Department for Medical Oncology, Oncology Institute of Vojvodina, University of Novi Sad, Novi Sad 21000, Serbia
| | - Milica Popovic
- Department for Nephrology and Clinical Immunology, Clinical Center of Vojvodina, University of Novi Sad, Novi Sad 21000, Serbia
| | - Ana Cvetanovic
- Department for Medical Oncology, Clinical Center of Nis, University of Nis, Nis 18000, Serbia
| | - Ivan Nikolic
- Department for Medical Oncology, Oncology Institute of Vojvodina, University of Novi Sad, Novi Sad 21000, Serbia
| | - Biljana Kukic
- Department for Medical Oncology, Oncology Institute of Vojvodina, University of Novi Sad, Novi Sad 21000, Serbia
| | - Dragana Petrovic
- Department for Medical Oncology, Oncology Institute of Vojvodina, Novi Sad 21000, Serbia
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Lenalidomide triggers T-cell effector functions in vivo in patients with follicular lymphoma. Blood Adv 2021; 5:2063-2074. [PMID: 33877296 DOI: 10.1182/bloodadvances.2020003774] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/08/2021] [Indexed: 02/08/2023] Open
Abstract
The immunomodulatory drug lenalidomide is used in patients with follicular lymphoma (FL) with the aim of stimulating T-cell antitumor immune response. However, little is known about the effects of lenalidomide on T-cell biology in vivo in patients with FL. We thus undertook an extensive longitudinal immunologic study, including phenotypic, transcriptomic, and functional analyses, on 44 first-line and 27 relapsed/refractory patients enrolled in the GALEN trial (Obinutuzumab Combined With Lenalidomide for Relapsed or Refractory Follicular B-Cell Lymphoma) to test the efficacy of lenalidomide and obinutuzumab combination in patients with FL. Lenalidomide rapidly and transiently induced an activated T-cell phenotype, including HLA-DR, Tim-3, CD137, and programmed cell death protein 1 (PD-1) upregulation. Furthermore, sequential RNA-sequencing of sorted PD-1+ and PD-1- T-cell subsets revealed that lenalidomide triggered a strong enrichment for several gene signatures related to effector memory T-cell features, including proliferation, antigen receptor signaling, and immune synapse restoration; all were validated at the phenotypic level and with ex vivo functional assays. Correlative analyses pinpointed a negative clinical impact of high effector T-cell and regulatory T-cell percentages before and during treatment. Our findings bring new insight in lenalidomide mechanisms of action at work in vivo and will fuel a new rationale for the design of combination therapies.
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12
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Role of Microenvironment in Non-Hodgkin Lymphoma: Understanding the Composition and Biology. ACTA ACUST UNITED AC 2021; 26:206-216. [PMID: 32496454 DOI: 10.1097/ppo.0000000000000446] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Lymphoma microenvironment is a dynamic and well-orchestrated network of various immune and stromal cells that is indispensable for tumor cell survival, growth, migration, immune escape, and drug resistance. Recent progress has enhanced our knowledge of the pivotal role of microenvironment in lymphomagenesis. Understanding the characteristics, functions, and contributions of various components of the tumor niche, along with its bidirectional interactions with tumor cells, is paramount. It offers the potential to identify new therapeutic targets with the ability to restore antitumor immune surveillance and eliminate the protumoral factors contributed by the tumor niche.
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13
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Extracellular vesicles (EVs): What we know of the mesmerizing roles of these tiny vesicles in hematological malignancies? Life Sci 2021; 271:119177. [PMID: 33577843 DOI: 10.1016/j.lfs.2021.119177] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 01/29/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Cancer is a complex disease in which a bidirectional collaboration between malignant cells and surrounding microenvironment creates an appropriate platform which ultimately facilitates the progression of the disease. The discovery of extracellular vesicles (EVs) was a turning point in the modern era of cancer biology, as their importance in human malignancies has set the stage to widen research interest in the field of cell-to-cell communication. The implication in short- and long-distance interaction via horizontally transfer of cellular components, ranging from non-coding RNAs to functional proteins, as well as stimulating target cells receptors by the means of ligands anchored on their membrane endows these "tiny vesicles with giant impacts" with incredible potential to re-educate normal tissues, and thus, to re-shape the surrounding niche. In this review, we highlight the pathogenic roles of EVs in human cancers, with an extensive focus on the recent advances in hematological malignancies.
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CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin's lymphoma and tumor-supportive follicular T helper cells. Nat Commun 2021; 12:240. [PMID: 33431832 PMCID: PMC7801647 DOI: 10.1038/s41467-020-20488-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 12/01/2020] [Indexed: 12/19/2022] Open
Abstract
CAR-T cell therapy targeting CD19 demonstrated strong activity against advanced B cell leukemia, however shows less efficacy against lymphoma with nodal dissemination. To target both B cell Non-Hodgkin’s lymphoma (B-NHLs) and follicular T helper (Tfh) cells in the tumor microenvironment (TME), we apply here a chimeric antigen receptor (CAR) that recognizes human CXCR5 with high avidity. CXCR5, physiologically expressed on mature B and Tfh cells, is also highly expressed on nodal B-NHLs. Anti-CXCR5 CAR-T cells eradicate B-NHL cells and lymphoma-supportive Tfh cells more potently than CD19 CAR-T cells in vitro, and they efficiently inhibit lymphoma growth in a murine xenograft model. Administration of anti-murine CXCR5 CAR-T cells in syngeneic mice specifically depletes endogenous and malignant B and Tfh cells without unexpected on-target/off-tumor effects. Collectively, anti-CXCR5 CAR-T cells provide a promising treatment strategy for nodal B-NHLs through the simultaneous elimination of lymphoma B cells and Tfh cells of the tumor-supporting TME. CAR-T cell therapy targeting CD19 is not as efficient to treat lymphoma with nodal dissemination as it is for B cell leukaemia. Here, the authors generate CAR-T cells against CXCR5 and show they inhibit tumour growth by depleting both B and follicular T helper cells in lymphoma models.
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15
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Augé H, Notarantonio AB, Morizot R, Quinquenel A, Fornecker LM, Hergalant S, Feugier P, Broséus J. Microenvironment Remodeling and Subsequent Clinical Implications in Diffuse Large B-Cell Histologic Variant of Richter Syndrome. Front Immunol 2020; 11:594841. [PMID: 33381116 PMCID: PMC7767850 DOI: 10.3389/fimmu.2020.594841] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/03/2020] [Indexed: 12/16/2022] Open
Abstract
Introduction Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in the context of Chronic Lymphocytic Leukemia (CLL), with a Diffuse Large B-Cell Lymphoma (DLBCL) histology in 95% cases. RS genomic landscape shares only a few features with de novo DLBCLs and is marked by a wide spectrum of cytogenetic abnormalities. Little is known about RS microenvironment. Therapeutic options and efficacy are limited, leading to a 12 months median overall survival. The new targeted treatments usually effective in CLL fail to obtain long-term remissions in RS. Methods We reviewed available PubMed literature about RS genomics, PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) pathway triggering and subsequent new therapeutic options. Results Data from about 207 patients from four landmark papers were compiled to build an overview of RS genomic lesions and point mutations. A number of these abnormalities may be involved in tumor microenvironment reshaping. T lymphocyte exhaustion through PD-L1 overexpression by tumor cells and subsequent PD-1/PD-L1 pathway triggering is frequently reported in solid cancers. This immune checkpoint inhibitor is also described in B lymphoid malignancies, particularly CLL: PD-1 expression is reported in a subset of prolymphocytes from the CLL lymph node proliferation centers. However, there is only few data about PD-1/PD-L1 pathway in RS. In RS, PD-1 expression is a hallmark of recently described « Regulatory B-cells », which interact with tumor microenvironment by producing inhibiting cytokines such as TGF-β and IL-10, impairing T lymphocytes anti-tumoral function. Based upon the discovery of high PD-1 expression on tumoral B lymphocyte from RS, immune checkpoint blockade therapies such as anti-PD-1 antibodies have been tested on small RS cohorts and provided heterogeneous but encouraging results. Conclusion RS genetic landscape and immune evasion mechanisms are being progressively unraveled. New protocols using targeted treatments such as checkpoint inhibitors as single agents or in combination with immunochemotherapy are currently being evaluated.
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Affiliation(s)
- Hélène Augé
- Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France.,Université de Lorraine, CHRU-Nancy, service d'hématologie clinique, pôle spécialités médicales, Nancy, France
| | - Anne-Béatrice Notarantonio
- Université de Lorraine, CHRU-Nancy, service d'hématologie clinique, pôle spécialités médicales, Nancy, France.,UMR7365 Ingénierie Moléculaire et Physiopathologie Articulaire (IMOPA), CNRS, Université de Lorraine, Nancy, France
| | - Romain Morizot
- Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France.,Université de Lorraine, CHRU-Nancy, service d'hématologie clinique, pôle spécialités médicales, Nancy, France
| | - Anne Quinquenel
- Département d'hématologie, Université de Reims Champagne-Ardenne, Reims, France.,Département d'hématologie clinique, Centre Hospitalier Universitaire de Reims, Reims, France
| | - Luc-Matthieu Fornecker
- Université de Strasbourg, Inserm, IRFAC/UMR-S1113, Strasbourg, France.,Département d'hématologie clinique, Institut de Cancérologie Strasbourg Europe, Strasbourg, France
| | - Sébastien Hergalant
- Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France
| | - Pierre Feugier
- Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France.,Université de Lorraine, CHRU-Nancy, service d'hématologie clinique, pôle spécialités médicales, Nancy, France
| | - Julien Broséus
- Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risque Environnementaux (N-GERE), Université de Lorraine, Nancy, France.,Université de Lorraine, CHRU-Nancy, service d'hématologie biologique, pôle laboratoires, Nancy, France
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16
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Ansell SM. Fundamentals of immunology for understanding immunotherapy for lymphoma. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2020; 2020:585-589. [PMID: 33275742 PMCID: PMC7727535 DOI: 10.1182/hematology.2020002537] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
An effective antitumor immune response in patients with lymphoma would eradicate the malignant B cells and cure the patient of the disease. This, however, does not occur, and a suboptimal antitumor response results in persistence and subsequent progression of the patient's disease. The goals of immunotherapy are therefore to restore an effective antitumor immune response by promoting immune recognition, optimizing immune activation, and supporting persistence of the immune response resulting in subsequent immunological memory. Multiple mechanisms, however, are present within the tumor microenvironment that account for an inadequate immune response. These include loss of major histocompatibility complex expression on tumor cells and subsequent inadequate antigen presentation, increased expression of immunosuppressive ligands on malignant cells, populations of immune cells with suppressive function present in the tumor, and cytokines secreted by the malignant cell or other cells in the microenvironment that promote immune exhaustion or suppress the immune response. Successful immunotherapeutic strategies are specifically addressing these issues by promoting antigen presentation, improving recognition of the malignant cell, directly activating T cells and natural killer cells, and blocking immune checkpoint signaling that would suppress the immune response. Many of these approaches have proven highly successful in patients with various subtypes of lymphoma and are now being incorporated into standard clinical practice.
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17
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Ansell SM. Fundamentals of immunology for understanding immunotherapy for lymphoma. Blood Adv 2020; 4:5863-5867. [PMID: 33232478 PMCID: PMC7686892 DOI: 10.1182/bloodadvances.2020002537] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 10/11/2020] [Indexed: 02/08/2023] Open
Abstract
An effective antitumor immune response in patients with lymphoma would eradicate the malignant B cells and cure the patient of the disease. This, however, does not occur, and a suboptimal antitumor response results in persistence and subsequent progression of the patient's disease. The goals of immunotherapy are therefore to restore an effective antitumor immune response by promoting immune recognition, optimizing immune activation, and supporting persistence of the immune response resulting in subsequent immunological memory. Multiple mechanisms, however, are present within the tumor microenvironment that account for an inadequate immune response. These include loss of major histocompatibility complex expression on tumor cells and subsequent inadequate antigen presentation, increased expression of immunosuppressive ligands on malignant cells, populations of immune cells with suppressive function present in the tumor, and cytokines secreted by the malignant cell or other cells in the microenvironment that promote immune exhaustion or suppress the immune response. Successful immunotherapeutic strategies are specifically addressing these issues by promoting antigen presentation, improving recognition of the malignant cell, directly activating T cells and natural killer cells, and blocking immune checkpoint signaling that would suppress the immune response. Many of these approaches have proven highly successful in patients with various subtypes of lymphoma and are now being incorporated into standard clinical practice.
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18
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Abstract
New treatment strategies in follicular lymphoma (FL) are driven by a deeper understanding of microenvironmental cues supporting lymphomagenesis, chemoresistance, and immuno-escape. These immune-mediated signaling pathways contribute to initial learnings and clinical successes with lenalidomide, the first, oral, non-chemotherapeutic immunomodulatory drug, combined with anti-CD20 antibodies. This combination of lenalidomide with rituximab showed similar efficacy to chemoimmunotherapy (CIT) in first-line patients requiring therapy, and is approved in relapsed/refractory FL. We review the biology supporting the rationale for adequate inhibitory receptor/ligand pathways targeting the tissue immune microenvironment of FL cells, and potential immunomodulating combinations to replace CIT in the near future.
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Affiliation(s)
- Loic Ysebaert
- Service d'Hematologie, Institut Universitaire du Cancer de Toulouse-Oncopole, Center for Cancer Research of Toulouse (CRCT), Inserm UMR1037, IUC-Toulouse-Oncopole, 1 Avenue Irene Joliot-Curie, Toulouse 31059, France
| | - Franck Morschhauser
- Univ. Lille, CHU Lille, ULR 7365 - GRITA - Groupe de Recherche Sur les Formes Injectables et les Technologies Associees, Lille F-59000, France.
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19
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Kawaguchi Y, Saito B, Nakata A, Matsui T, Sasaki Y, Shimada S, Abe M, Watanuki M, Baba Y, Murai S, Arai N, Fujiwara S, Kabasawa N, Tsukamoto H, Uto Y, Yanagisawa K, Hattori N, Harada H, Nakamaki T. Elevated C-reactive protein level is associated with poor prognosis in follicular lymphoma patients undergoing rituximab-containing chemotherapy. Int J Hematol 2020; 112:341-348. [PMID: 32524308 DOI: 10.1007/s12185-020-02910-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 05/04/2020] [Accepted: 05/27/2020] [Indexed: 11/30/2022]
Abstract
Although follicular lymphoma (FL) is a pathological entity characterized by relatively uniform histological and molecular findings, its clinical course is highly variable. Establishment of therapeutic strategies based on a simple and practical prognostic model is important. C-reactive protein (CRP) is an adverse prognostic marker for various tumors and aggressive lymphomas. However, the significance of serum CRP levels as a prognostic index in low-grade lymphomas, such as FL, has not been thoroughly investigated. We retrospectively analyzed the relationship between serum CRP levels at diagnosis and the prognosis in patients with FL (n = 61) undergoing rituximab-containing chemotherapy. Elevated CRP levels showed a significant association with elevated fibrinogen (P = 0.002) in univariate analysis. Patients with higher CRP levels (> 5 mg/L) had a significantly shorter progression-free survival in multivariate analysis (P = 0.044). We concluded that serum CRP levels are important in prognostic stratification of patients with FL.
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Affiliation(s)
- Yukiko Kawaguchi
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan.
| | - Bungo Saito
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Ayaka Nakata
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Tomoharu Matsui
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Yohei Sasaki
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Shotaro Shimada
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Maasa Abe
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Megumi Watanuki
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Yuta Baba
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - So Murai
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Nana Arai
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Shun Fujiwara
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Nobuyuki Kabasawa
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Hiroyuki Tsukamoto
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Yui Uto
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Kouji Yanagisawa
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Norimichi Hattori
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
| | - Hiroshi Harada
- Division of Hematology, Department of Medicine, Showa University Fujigaoka Hospital, Kanagawa, Japan
| | - Tsuyoshi Nakamaki
- Division of Hematology, Department of Medicine, Showa University School of Medicine, 142-8666 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, Japan
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Fernandes M, Teixeira AL, Medeiros R. The opportunistic effect of exosomes on Non-Hodgkin Lymphoma microenvironment modulation. Crit Rev Oncol Hematol 2019; 144:102825. [PMID: 31734546 DOI: 10.1016/j.critrevonc.2019.102825] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 10/20/2019] [Accepted: 10/22/2019] [Indexed: 12/14/2022] Open
Abstract
There has been a shift in the paradigm of Non-Hodgkin lymphomas, changing from the classical genetic aberration-based model to a more complex and dynamic model involving tumor microenvironment interactions. In this instance, exosomes have emerged as important mediators in intercellular communication by providing survival and proliferation signals, licensing immune evasion and acquisition of drug resistance. The capability to transfer molecular cargo made exosomes a focus of research to understand cancer pathogenesis and its progression pathways. Several studies identified exosomes transporting tumor-released components in peripheral blood and focused on understanding their clinical relevance in the diagnosis, prognostic and in monitoring cancer progression. Moreover, due to their biophysical properties and physiological function, exosomes have drawn attention as potential therapeutic target and drug delivery vehicles. This review will discuss the function of exosomes in Non-Hodgkin lymphomagenesis, highlight their potential as diagnosis and prognosis biomarkers, and as new therapeutic opportunities in lymphoma management.
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Affiliation(s)
- Mara Fernandes
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal; Faculty of Medicine, University of Porto (FMUP), Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Research Department, LPCC-Portuguese League against Cancer- Northern Branch (Liga Portuguesa Contra o Cancro-Núcleo Regional do Norte), Estrada Interior da Circunvalação 6657, 4200-172 Porto, Portugal
| | - Ana Luísa Teixeira
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal; Faculty of Medicine, University of Porto (FMUP), Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Research Department, LPCC-Portuguese League against Cancer- Northern Branch (Liga Portuguesa Contra o Cancro-Núcleo Regional do Norte), Estrada Interior da Circunvalação 6657, 4200-172 Porto, Portugal; CEBIMED, Faculty of Health Sciences, Fernando Pessoa University, Praça de 9 de Abril 349, 4249-004 Porto, Portugal.
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21
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Höpken UE, Rehm A. Targeting the Tumor Microenvironment of Leukemia and Lymphoma. Trends Cancer 2019; 5:351-364. [DOI: 10.1016/j.trecan.2019.05.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 04/29/2019] [Accepted: 05/03/2019] [Indexed: 12/13/2022]
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22
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Abstract
PURPOSE OF REVIEW In addition to the recent progresses in the description of the genetic landscape of B-cell non-Hodgkin's lymphomas, tumor microenvironment has progressively emerged as a central determinant of early lymphomagenesis, subclonal evolution, drug resistance, and late progression/transformation. The purpose of this review is to outline the most recent findings regarding malignant B-cell niche composition and organization supporting direct and indirect tumor-promoting functions of lymphoma microenvironment. RECENT FINDINGS Lymphoma supportive niche integrates a dynamic and orchestrated network of immune and stromal cell subsets producing, with a high level of spatial and kinetic heterogeneity, extracellular and membrane factors regulating tumor migration, survival, proliferation, immune escape, as well as tumor microarchitecture, and mechanical constraints. Some recent insights have improved our understanding of these various components of lymphoma microenvironment, taking into account the mechanisms underlying the coevolution of malignant and nonmalignant cells within the tumor niche. SUMMARY Deciphering tumor niche characteristics, functions, and origin could offer new therapeutic opportunities through the targeting of pivotal cellular and molecular components of the supportive microenvironment, favoring immune cell reactivation and infiltration, and/or limiting tumor retention within this protective niche.
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23
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Navarro-Tableros V, Gomez Y, Camussi G, Brizzi MF. Extracellular Vesicles: New Players in Lymphomas. Int J Mol Sci 2018; 20:E41. [PMID: 30583481 PMCID: PMC6337615 DOI: 10.3390/ijms20010041] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 12/17/2018] [Accepted: 12/18/2018] [Indexed: 12/12/2022] Open
Abstract
Lymphomas are heterogeneous diseases, and the term includes a number of histological subtypes that are characterized by different clinical behavior and molecular phenotypes. Valuable information on the presence of lymphoma cell-derived extracellular vesicles (LCEVs) in the bloodstream of patients suffering from this hematological cancer has recently been provided. In particular, it has been reported that the number and phenotype of LCEVs can both change as the disease progresses, as well as after treatment. Moreover, the role that LCEVs play in driving tumor immune escape has been reported. This makes LCEVs potential novel clinical tools for diagnosis, disease progression, and chemoresistance. LCEVs express surface markers and convey specific molecules in accordance with their cell of origin, which can be used as targets and thus lead to the development of specific therapeutics. This may be particularly relevant since circulating LCEVs are known to save lymphoma cells from anti-cluster of differentiation (CD)20-induced complement-dependent cytotoxicity. Therefore, effort should be directed toward investigating the feasibility of using LCEVs as predictive biomarkers of disease progression and/or response to treatment that can be translated to clinical use. The use of liquid biopsies in combination with serum EV quantification and cargo analysis have been also considered as potential approaches that can be pursued in the future. Upcoming research will also focus on the identification of specific molecular targets in order to generate vaccines and/or antibodies against LCEVs. Finally, the removal of circulating LCEVs has been proposed as a simple and non-invasive treatment approach. We herein provide an overview of the role of LCEVs in lymphoma diagnosis, immune tolerance, and drug resistance. In addition, alternative protocols that utilize LCEVs as therapeutic targets are discussed.
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Affiliation(s)
- Victor Navarro-Tableros
- 2i3T Società per la gestione dell'incubatore di imprese e per il trasferimento tecnologico Scarl, University of Turin, Turin 10126, Italy.
| | - Yonathan Gomez
- Department of Medical Sciences, University of Turin, Turin 10126, Italy.
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin 10126, Italy.
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Kumar D, Xu ML. Microenvironment Cell Contribution to Lymphoma Immunity. Front Oncol 2018; 8:288. [PMID: 30101129 PMCID: PMC6073855 DOI: 10.3389/fonc.2018.00288] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 07/09/2018] [Indexed: 12/11/2022] Open
Abstract
Lymphoma microenvironment is a complex system composed of stromal cells, blood vessels, immune cells as well as extracellular matrix, cytokines, exosomes, and chemokines. In this review, we describe the function, localization, and interactions between various cellular components. We also summarize their contribution to lymphoma immunity in the era of immunotherapy. Publications were identified from searching Pubmed. Primary literature was carefully evaluated for replicability before incorporating into the review. We describe the roles of mesenchymal stem/stromal cells (MSCs), lymphoma-associated macrophages (LAMs), dendritic cells, cytotoxic T cells, PD-1 expressing CD4+ tumor infiltrating lymphocytes (TILs), T-cells expressing markers of exhaustion such as TIM-3 and LAG-3, regulatory T cells, and natural killer cells. While it is not in itself a cell, we also include a brief overview of the lymphoma exosome and how it contributes to anti-tumor effect as well as immune dysfunction. Understanding the cellular players that comprise the lymphoma microenvironment is critical to developing novel therapeutics that can help block the signals for immune escape and promote tumor surveillance. It may also be the key to understanding mechanisms of resistance to immune checkpoint blockade and immune-related adverse events due to certain types of immunotherapy.
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Affiliation(s)
- Deepika Kumar
- Departments of Pathology & Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Mina L Xu
- Departments of Pathology & Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States
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