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Jordan MA, Morschl J, Autenrieth SE. Dendritic cells in multiple myeloma: from immune evasion to therapeutic potential. Front Immunol 2025; 16:1575509. [PMID: 40313957 PMCID: PMC12043573 DOI: 10.3389/fimmu.2025.1575509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/02/2025] [Indexed: 05/03/2025] Open
Abstract
Multiple myeloma (MM) is a type of hematologic cancer characterized by the uncontrolled clonal expansion of plasma cells in the bone marrow (BM). This leads to significant dysfunction and suppression of the immune system in affected patients. Myeloma cells employ sophisticated strategies to manipulate immune and non-immune cells, evading immune surveillance and enhancing their survival. One key factor in this evasion is the disruption of dendritic cell (DC)-mediated immune mechanisms. Extensive evidence indicates that in the presence of myeloma cells, DC numbers are notably reduced, and their phenotype and function are altered, impairing their ability to present antigens and activate robust T-cell responses effectively. Despite rapid advances in MM treatment, with promising strategies such as DC-based vaccines being already achieved, DC dysfunction remains a substantial hurdle, associated with or contributing to poor therapeutic outcomes, disease relapse, and MM's persistence as an incurable disease. To address these challenges, it is essential to understand the intricate mechanisms through which myeloma cells transform DCs into their "accomplices," undermining immune responses. This review comprehensively summarizes the current understanding of the role of DCs in MM. Additionally, it evaluates the potential of DCs in anti-MM immunotherapy, discussing persistent challenges and highlighting emerging perspectives that may lead to promising breakthroughs for improved patient outcomes.
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Abbaszadeh M, Naseri B, Taghizadeh-Teymorloei M, Mardi A, Javan MR, Masoumi J, Ghorbaninezhad F, Hatami‐Sadr A, Tural Ş, Baradaran B, Sadeghi MR. Overview of dendritic cells subsets and their involvement in immune-related pathological disease. BIOIMPACTS : BI 2025; 15:30671. [PMID: 40256217 PMCID: PMC12008504 DOI: 10.34172/bi.30671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/01/2024] [Accepted: 11/19/2024] [Indexed: 04/22/2025]
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) in linking innate and adaptive immune responses. In addition to presenting antigens to T cells, DCs must also provide co-stimulatory signals along with cytokines for T cells to induce an appropriate cellular immune response. Tolerance is also established and maintained by DCs under homeostatic circumstances. There is remarkable phenotypic heterogeneity in DCs, each with different functional flexibility and specific expression of various markers. The three primary categories of DCs comprise conventional DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs). Langerhans cells (LCs) are another type of DCs, which are found in the skin's epidermal layer. DCs may be positioned or triggered inappropriately as a result of dysregulation of DC. This phenomenon can cause an imbalance in immune responses and even immune-related pathological disorders, i.e., autoimmune diseases and malignancies. Herein, by reviewing the ontogeny, biology, characteristics, and function of DCs subsets in immune system, we discuss the contribution of these cells in the mentioned immune-related disorders.
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Affiliation(s)
- Mohsen Abbaszadeh
- Molecular Medicine Department, Faculty of advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahar Naseri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadeh-Teymorloei
- Molecular Medicine Department, Faculty of advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhossein Mardi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Javan
- Department of Immunology, Faculty of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Javad Masoumi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farid Ghorbaninezhad
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Şengül Tural
- Mayis University, Faculty of Medicine, Department of Medical Biology, Samsun, Turkey
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Sadeghi
- Molecular Medicine Department, Faculty of advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Shil RK, Mohammed NBB, Dimitroff CJ. Galectin-9 - ligand axis: an emerging therapeutic target for multiple myeloma. Front Immunol 2024; 15:1469794. [PMID: 39386209 PMCID: PMC11461229 DOI: 10.3389/fimmu.2024.1469794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 09/09/2024] [Indexed: 10/12/2024] Open
Abstract
Galectin-9 (Gal-9) is a tandem-repeat galectin with diverse roles in immune homeostasis, inflammation, malignancy, and autoimmune diseases. In cancer, Gal-9 displays variable expression patterns across different tumor types. Its interactions with multiple binding partners, both intracellularly and extracellularly, influence key cellular processes, including immune cell modulation and tumor microenvironment dynamics. Notably, Gal-9 binding to cell-specific glycoconjugate ligands has been implicated in both promoting and suppressing tumor progression. Here, we provide insights into Gal-9 and its involvement in immune homeostasis and cancer biology with an emphasis on multiple myeloma (MM) pathophysiology, highlighting its complex and context-dependent dual functions as a pro- and anti-tumorigenic molecule and its potential implications for therapy in MM patients.
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Affiliation(s)
- Rajib K. Shil
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Norhan B. B. Mohammed
- The Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, United States
- Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Charles J. Dimitroff
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
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Ortiz V, Loeuillard E. Rethinking Immune Check Point Inhibitors Use in Liver Transplantation: Implications and Resistance. Cell Mol Gastroenterol Hepatol 2024; 19:101407. [PMID: 39326581 PMCID: PMC11609388 DOI: 10.1016/j.jcmgh.2024.101407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 09/18/2024] [Accepted: 09/18/2024] [Indexed: 09/28/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, including the two most common liver tumors, hepatocellular carcinoma and cholangiocarcinoma, but their use in the peri-transplantation period is controversial. ICI therapy aims to heighten cytotoxic T lymphocytes response against tumors. However, tumor recurrence is common owing to tumor immune response escape involving ablation of CTL response by interfering with antigen presentation, triggering CLT apoptosis and inducing epigenetic changes that promote ICI therapy resistance. ICI can also affect tissue resident memory T cell population, impact tolerance in the post-transplant period, and induce acute inflammation risking graft survival post-transplant. Their interaction with immunosuppression may be key in reducing tumor burden and may thus, require multimodal therapy to treat these tumors. This review summarizes ICI use in the liver transplantation period, their impact on tolerance and resistance, and new potential therapies for combination or sequential treatments for liver tumors.
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Affiliation(s)
- Vivian Ortiz
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, Missouri.
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Pandey VK, Premkumar K, Kundu P, Shankar BS. PGE2 induced miR365/IL-6/STAT3 signaling mediates dendritic cell dysfunction in cancer. Life Sci 2024; 350:122751. [PMID: 38797363 DOI: 10.1016/j.lfs.2024.122751] [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: 01/25/2024] [Revised: 05/10/2024] [Accepted: 05/24/2024] [Indexed: 05/29/2024]
Abstract
AIM To understand the mechanism of prostaglandin E2 (PGE2)-mediated immunosuppression in dendritic cells (DCs). MAIN METHODS In vivo experiments were conducted on 4T1 tumor bearing mice (TBM). In vitro experiments were performed in bone marrow-derived DCs (BMDCs), or spleen cells. Cytokines were monitored by ELISA/ELIspot. Gene expression was monitored by RT-PCR/flow cytometry. KEY FINDINGS In silico, in vitro, and in vivo experiments in 4T1 TBM revealed that PGE2 induced IL-6/pSTAT3 signaling through EP4 receptors in DCs, resulting in their dysfunction. These effects were reversed by EP4 antibody neutralization, EP4 antagonist, and STAT3 inhibitory peptides. PGE2 induced IL-6 was regulated by miR-365, as its mimic inhibited PGE2 induced IL-6 and the inhibitor increased lL-6 levels in DC. Bio-informatic analysis in human mammary cancers also revealed a strong compared co-relation between PGE2 and IL-6 (Correlation AnalyzeR) (R = 0.94). Mice bearing PTGS-2 KD 4T1 tumors had decreased tumor burden, PGE2, EP4, IL-6, and pSTAT3 signaling, along with improved DCs and T cell functions. Treatment of mice with a cyclooxygenase-2 (COX-2) inhibitor or EP4 antagonist decreased tumor burden, and this effect of EP4 antagonist was abrogated upon in vivo depletion of CD11c cells, indicating the crucial role of PGE2 signaling in DCs in tumor progression. SIGNIFICANCE In summary, our data highlights the importance of dendritic cells in mediating PGE2-mediated immunosuppression and the use of EP4 or STAT3 inhibitors or miR365 mimics can restore immunogenicity in cancer.
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Affiliation(s)
- Vipul K Pandey
- Immunology Section, Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India
| | - Kavitha Premkumar
- Immunology Section, Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India
| | - Priya Kundu
- Immunology Section, Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India
| | - Bhavani S Shankar
- Immunology Section, Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400 094, India.
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Jen WY, Konopleva M, Pemmaraju N. Tagraxofusp, a first-in-class CD123-targeted agent: Five-year postapproval comprehensive review of the literature. Cancer 2024; 130:2260-2271. [PMID: 38620053 DOI: 10.1002/cncr.35315] [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: 02/22/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 04/17/2024]
Abstract
Tagraxofusp is a first-in-class CD123-directed conjugate of an amended diphtheria toxin platform and recombinant interleukin 3. Binding and subsequent internalization of the drug result in cell death via disruption of intracellular protein synthesis. CD123 is a surface marker that is expressed in several hematological malignancies, especially blastic plasmacytoid dendritic cell neoplasm (BPDCN), where its expression is ubiquitous. A pivotal study of tagraxofusp in BPDCN resulted in its approval for the treatment of BPDCN, the first treatment approved for this indication. Since the introduction of tagraxofusp, research has focused on the management of adverse effects, combination therapy to improve outcomes in fit patients, and dosing and combination strategies to mitigate toxicities while preserving efficacy, especially among older patients. The successful targeting of CD123 in BPDCN has also encouraged research into a variety of other CD123-positive hematological neoplasms, including acute myeloid leukemia (AML), and informed the development of other novel agents targeting CD123. This review examines the clinical data leading to the development and approval of tagraxofusp in BPDCN, how it is being used in combination to improve outcomes in BPDCN and AML, and its developing role in other hematological malignancies.
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Affiliation(s)
- Wei-Ying Jen
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Marina Konopleva
- Department of Oncology, Montefiore Einstein Comprehensive Cancer Center, Bronx, New York, USA
| | - Naveen Pemmaraju
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Malard F, Neri P, Bahlis NJ, Terpos E, Moukalled N, Hungria VTM, Manier S, Mohty M. Multiple myeloma. Nat Rev Dis Primers 2024; 10:45. [PMID: 38937492 DOI: 10.1038/s41572-024-00529-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/16/2024] [Indexed: 06/29/2024]
Abstract
Multiple myeloma (MM) is a haematological lymphoid malignancy involving tumoural plasma cells and is usually characterized by the presence of a monoclonal immunoglobulin protein. MM is the second most common haematological malignancy, with an increasing global incidence. It remains incurable because most patients relapse or become refractory to treatments. MM is a genetically complex disease with high heterogeneity that develops as a multistep process, involving acquisition of genetic alterations in the tumour cells and changes in the bone marrow microenvironment. Symptomatic MM is diagnosed using the International Myeloma Working Group criteria as a bone marrow infiltration of ≥10% clonal plasma cells, and the presence of at least one myeloma-defining event, either standard CRAB features (hypercalcaemia, renal failure, anaemia and/or lytic bone lesions) or biomarkers of imminent organ damage. Younger and fit patients are considered eligible for transplant. They receive an induction, followed by consolidation with high-dose melphalan and autologous haematopoietic cell transplantation, and maintenance therapy. In older adults (ineligible for transplant), the combination of daratumumab, lenalidomide and dexamethasone is the preferred option. If relapse occurs and requires further therapy, the choice of therapy will be based on previous treatment and response and now includes immunotherapies, such as bi-specific monoclonal antibodies and chimeric antigen receptor T cell therapy.
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Affiliation(s)
- Florent Malard
- Sorbonne Université, Centre de Recherche Saint-Antoine INSERM UMRs938, Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France.
| | - Paola Neri
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada
| | - Nizar J Bahlis
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada
| | - Evangelos Terpos
- Department of Clinical Therapeutics, Alexandra General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Nour Moukalled
- Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | | | - Salomon Manier
- Department of Hematology, Lille University Hospital and INSERM UMR-S1277 and CNRS UMR9020, Lille, France
| | - Mohamad Mohty
- Sorbonne Université, Centre de Recherche Saint-Antoine INSERM UMRs938, Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France.
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Kim IW, Yoon AR, Hong J, Kasala D, Yun CO. Synergistic antitumor immune response mediated by paclitaxel-conjugated nanohybrid oncolytic adenovirus with dendritic cell therapy. Front Immunol 2024; 15:1355566. [PMID: 38835775 PMCID: PMC11148213 DOI: 10.3389/fimmu.2024.1355566] [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: 12/14/2023] [Accepted: 05/06/2024] [Indexed: 06/06/2024] Open
Abstract
Dendritic cell (DC)-based vaccines have emerged as a promising strategy in cancer immunotherapy due to low toxicity. However, the therapeutic efficacy of DC as a monotherapy is insufficient due to highly immunosuppressive tumor environment. To address these limitations of DC as immunotherapeutic agent, we have developed a polymeric nanocomplex incorporating (1) oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) and (2) arginine-grafted bioreducible polymer with PEGylated paclitaxel (APP) to restore antitumor immune surveillance function in tumor milieu and potentiate immunostimulatory attributes of DC vaccine. Nanohybrid complex (oAd/APP) in combination with DC (oAd/APP+DC) induced superior expression level of antitumor cytokines (IL-12, GM-CSF, and interferon gamma) than either oAd/APP or DC monotherapy in tumor tissues, thus resulting in superior intratumoral infiltration of both endogenous and exogenous DCs. Furthermore, oAd/APP+DC treatment led superior migration of DC to secondary lymphoid organs, such as draining lymph nodes and spleen, in comparison with either monotherapy. Superior migration profile of DCs in oAd/APP+DC treatment group resulted in more prolific activation of tumor-specific T cells in these lymphoid organs and greater intratumoral infiltration of T cells. Additionally, oAd/APP+DC treatment led to lower subset of tumor infiltrating lymphocytes and splenocytes being immunosuppressive regulatory T cells than any other treatment groups. Collectively, oAd/APP+DC led to superior induction of antitumor immune response and amelioration of immunosuppressive tumor microenvironment to elicit potent tumor growth inhibition than either monotherapy.
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Affiliation(s)
- In-Wook Kim
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea
| | - A-Rum Yoon
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea
| | - JinWoo Hong
- GeneMedicine CO., Ltd., Seoul, Republic of Korea
| | - Dayananda Kasala
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
| | - Chae-Ok Yun
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, Republic of Korea
- Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea
- GeneMedicine CO., Ltd., Seoul, Republic of Korea
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Harandi H, Fallahtafti P, Karimi A, Hashemi SM, Mahalleh M, Ashouri M, Salehi MA, Hoveidaei A. Examining the immunological responses to COVID-19 vaccination in multiple myeloma patients: a systematic review and meta-analysis. BMC Geriatr 2024; 24:411. [PMID: 38720296 PMCID: PMC11080142 DOI: 10.1186/s12877-024-05006-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 04/24/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Impaired immune response in multiple myeloma renders the patients vulnerable to infections, such as COVID-19, and may cause worse response to vaccines. Researchers should analyze this issue to enable the planning for special preventive measures, such as increased booster doses. Therefore, this meta-analysis aimed to evaluate the response and efficacy of COVID-19 vaccines in patients with multiple myeloma. METHODS This meta-analysis followed PRISMA 2020 guidelines, conducting a comprehensive database search using specified keywords. Study selection involved a two-phase title/abstract and full-text screening process. Data extraction was performed by two researchers, and statistical analysis involved meta-analysis, subgroup analysis based on vaccine dosage and study time, random effects meta-regression, and heterogeneity testing using the Q test. RESULTS The meta-analysis revealed that patients with multiple myeloma (MM) had a lower likelihood of developing detectable antibodies after COVID-19 vaccination compared to healthy controls (Log odds ratio with 95% CI: -3.34 [-4.08, -2.60]). The analysis of antibody response after different doses showed consistent lower seropositivity in MM patients (after first dose: -2.09, [-3.49, -0.69], second: -3.80, 95%CI [-4.71, -3.01], a booster dose: -3.03, [-5.91, -0.15]). However, there was no significant difference in the mean level of anti-S antibodies between MM patients and controls (Cohen's d -0.72, [-1.86, 0.43]). Evaluation of T-cell responses indicated diminished T-cell-mediated immunity in MM patients compared to controls. Seven studies reported clinical response, with breakthrough infections observed in vaccinated MM patients. CONCLUSIONS These findings highlight the impaired humoral and cellular immune responses in MM patients after COVID-19 vaccination, suggesting the need for further investigation and potential interventions.
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Affiliation(s)
- Hamid Harandi
- Research Center for Antibiotic Stewardship and Antimicrobial Resistance, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Fallahtafti
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirali Karimi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | | | - Mehrdad Mahalleh
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Ashouri
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Armin Hoveidaei
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Hughes D, Yong K, Ramasamy K, Stern S, Boyle E, Ashcroft J, Basheer F, Rabin N, Pratt G. Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper. Br J Haematol 2024; 204:1193-1206. [PMID: 38393718 DOI: 10.1111/bjh.19333] [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: 11/22/2023] [Revised: 01/20/2024] [Accepted: 01/28/2024] [Indexed: 02/25/2024]
Abstract
Multiple myeloma is a bone marrow-based plasma cell tumour that develops from asymptomatic pre-cursor conditions smouldering myeloma and monoclonal gammopathy of uncertain significance and all are characterised by the presence of a monoclonal protein in the blood. Diagnosis and distinction between these conditions is based on blood tests, the bone marrow biopsy and cross sectional imaging. There are various risk stratification models that group patients with smouldering myeloma into risk groups based on risk of progression to symptomatic disease. Management is mainly observational for patients with smouldering myeloma although clinical trials for high-risk disease may be available. Restaging is required if evidence for progression.
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Affiliation(s)
- Daniel Hughes
- UCL Cancer Institute, University College London, London, UK
| | - Kwee Yong
- UCL Cancer Institute, University College London, London, UK
| | - Karthik Ramasamy
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Oxford Translational Myeloma Centre, NDORMS, University of Oxford, Oxford, UK
| | - Simon Stern
- Epsom and St Helier University Hospitals NHS Trust, Sutton, UK
| | - Eileen Boyle
- UCL Cancer Institute, University College London, London, UK
| | - John Ashcroft
- The Mid Yorkshire Teaching Hospitals NHS Trust, Wakefield, UK
| | - Faisal Basheer
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Neil Rabin
- University College London Hospitals, London, UK
| | - Guy Pratt
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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11
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Vo MC, Jung SH, Nguyen VT, Tran VDH, Ruzimurodov N, Kim SK, Nguyen XH, Kim M, Song GY, Ahn SY, Ahn JS, Yang DH, Kim HJ, Lee JJ. Exploring cellular immunotherapy platforms in multiple myeloma. Heliyon 2024; 10:e27892. [PMID: 38524535 PMCID: PMC10957441 DOI: 10.1016/j.heliyon.2024.e27892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 03/07/2024] [Accepted: 03/07/2024] [Indexed: 03/26/2024] Open
Abstract
Despite major advances in therapeutic platforms, most patients with multiple myeloma (MM) eventually relapse and succumb to the disease. Among the novel therapeutic options developed over the past decade, genetically engineered T cells have a great deal of potential. Cellular immunotherapies, including chimeric antigen receptor (CAR) T cells, are rapidly becoming an effective therapeutic modality for MM. Marrow-infiltrating lymphocytes (MILs) derived from the bone marrow of patients with MM are a novel source of T cells for adoptive T-cell therapy, which robustly and specifically target myeloma cells. In this review, we examine the recent innovations in cellular immunotherapies, including the use of dendritic cells, and cellular tools based on MILs, natural killer (NK) cells, and CAR T cells, which hold promise for improving the efficacy and/or reducing the toxicity of treatment in patients with MM.
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Affiliation(s)
- Manh-Cuong Vo
- Institute of Research and Development, Duy Tan University, Danang, Viet Nam
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea
- Vaxcell-Bio Therapeutics, Hwasun, Jeollanamdo, Republic of Korea
| | - Sung-Hoon Jung
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Hwasun, Jeollanamdo, Republic of Korea
| | - Van-Tan Nguyen
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea
| | - Van-Dinh-Huan Tran
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea
| | - Nodirjon Ruzimurodov
- Institute of Immunology and Human Genomics of the Academy of Sciences of the Republic of Uzbekistan, Uzbekistan
| | - Sang Ki Kim
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea
- Department of Laboratory and Companion Animal Science, College of Industrial Science, Kongju National University, Yesan-eup, Yesan-gun, Chungnam, Republic of Korea
- Vaxcell-Bio Therapeutics, Hwasun, Jeollanamdo, Republic of Korea
| | - Xuan-Hung Nguyen
- Hi-Tech Center and Vinmec-VinUni Institute of Immunology, Vinmec Healthcare system, Hanoi, Vietnam
| | - Mihee Kim
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Hwasun, Jeollanamdo, Republic of Korea
| | - Ga-Young Song
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Hwasun, Jeollanamdo, Republic of Korea
| | - Seo-Yeon Ahn
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Hwasun, Jeollanamdo, Republic of Korea
| | - Jae-Sook Ahn
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Hwasun, Jeollanamdo, Republic of Korea
| | - Deok-Hwan Yang
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Hwasun, Jeollanamdo, Republic of Korea
| | - Hyeoung-Joon Kim
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Hwasun, Jeollanamdo, Republic of Korea
| | - Je-Jung Lee
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Hwasun, Jeollanamdo, Republic of Korea
- Vaxcell-Bio Therapeutics, Hwasun, Jeollanamdo, Republic of Korea
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12
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Wang C, Wang W, Wang M, Deng J, Sun C, Hu Y, Luo S. Different evasion strategies in multiple myeloma. Front Immunol 2024; 15:1346211. [PMID: 38464531 PMCID: PMC10920326 DOI: 10.3389/fimmu.2024.1346211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/09/2024] [Indexed: 03/12/2024] Open
Abstract
Multiple myeloma is the second most common malignant hematologic malignancy which evolved different strategies for immune escape from the host immune surveillance and drug resistance, including uncontrolled proliferation of malignant plasma cells in the bone marrow, genetic mutations, or deletion of tumor antigens to escape from special targets and so. Therefore, it is a big challenge to efficiently treat multiple myeloma patients. Despite recent applications of immunomodulatory drugs (IMiDS), protease inhibitors (PI), targeted monoclonal antibodies (mAb), and even hematopoietic stem cell transplantation (HSCT), it remains hardly curable. Summarizing the possible evasion strategies can help design specific drugs for multiple myeloma treatment. This review aims to provide an integrative overview of the intrinsic and extrinsic evasion mechanisms as well as recently discovered microbiota utilized by multiple myeloma for immune evasion and drug resistance, hopefully providing a theoretical basis for the rational design of specific immunotherapies or drug combinations to prevent the uncontrolled proliferation of MM, overcome drug resistance and improve patient survival.
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Affiliation(s)
| | | | | | | | | | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shanshan Luo
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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13
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Kostecki KL, Iida M, Crossman BE, Salgia R, Harari PM, Bruce JY, Wheeler DL. Immune Escape Strategies in Head and Neck Cancer: Evade, Resist, Inhibit, Recruit. Cancers (Basel) 2024; 16:312. [PMID: 38254801 PMCID: PMC10814769 DOI: 10.3390/cancers16020312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Head and neck cancers (HNCs) arise from the mucosal lining of the aerodigestive tract and are often associated with alcohol use, tobacco use, and/or human papillomavirus (HPV) infection. Over 600,000 new cases of HNC are diagnosed each year, making it the sixth most common cancer worldwide. Historically, treatments have included surgery, radiation, and chemotherapy, and while these treatments are still the backbone of current therapy, several immunotherapies have recently been approved by the Food and Drug Administration (FDA) for use in HNC. The role of the immune system in tumorigenesis and cancer progression has been explored since the early 20th century, eventually coalescing into the current three-phase model of cancer immunoediting. During each of the three phases-elimination, equilibrium, and escape-cancer cells develop and utilize multiple strategies to either reach or remain in the final phase, escape, at which point the tumor is able to grow and metastasize with little to no detrimental interference from the immune system. In this review, we summarize the many strategies used by HNC to escape the immune system, which include ways to evade immune detection, resist immune cell attacks, inhibit immune cell functions, and recruit pro-tumor immune cells.
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Affiliation(s)
- Kourtney L. Kostecki
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
| | - Mari Iida
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
| | - Bridget E. Crossman
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
| | - Ravi Salgia
- Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA;
| | - Paul M. Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA;
| | - Justine Y. Bruce
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA;
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Deric L. Wheeler
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA;
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14
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Norton SE, Khong T, Ramachandran M, Highton AJ, Ward‐Hartstonge KA, Shortt J, Spencer A, Kemp RA. Changes in immune cell populations following KappaMab, lenalidomide and low-dose dexamethasone treatment in multiple myeloma. Clin Transl Immunology 2023; 12:e1478. [PMID: 38034081 PMCID: PMC10688504 DOI: 10.1002/cti2.1478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 08/19/2023] [Accepted: 11/13/2023] [Indexed: 12/02/2023] Open
Abstract
Objectives Lenalidomide (LEN) is used to treat multiple myeloma (MM) and shows in vitro synergy with KappaMab (KM), a chimeric antibody specific for Kappa Myeloma antigen, an antigen exclusively expressed on the surface of kappa-restricted MM cells. Lenalidomide, dexamethasone (DEX) and KM control MM via multiple immunomodulatory mechanisms; however, there are several additional effects of the drug combination on immune cells. Lenalidomide can increase T cell and NKT cell cytotoxicity and dendritic cell (DC) activation in vitro. We investigated the immune cell populations in bone marrow of patients treated with KM, LEN and low-dose DEX in kappa-restricted relapsed/refractory MM ex vivo and assessed association of those changes with patient outcome. Methods A cohort (n = 40) of patients with kappa-restricted relapsed/refractory MM, treated with KM, LEN and low-dose DEX, was analysed using a mass cytometry panel that allowed identification of immune cell subsets. Clustering analyses were used to determine significant changes in immune cell populations at time periods after treatment. Results We found changes in five DC and 17 T-cell populations throughout treatment. We showed an increase in activated conventional DC populations, a decrease in immature/precursor DC populations, a decrease in activated CD4 T cells and an increase in effector-memory CD4 T cells and effector CD8 T cells, indicating an activated immune response. Conclusion These data characterise the effects of LEN, DEX, and KM treatment on non-target immune cells in MM. Treatment may support destruction of MM cells by both direct action and indirect mechanisms via immune cells.
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Affiliation(s)
| | - Tiffany Khong
- Myeloma Research Group, Australian Centre for Blood DiseasesAlfred Hospital‐Monash UniversityMelbourneVICAustralia
- Department of Clinical Haematology and Stem Cell TransplantationAlfred HospitalMelbourneVICAustralia
| | - Malarmathy Ramachandran
- Myeloma Research Group, Australian Centre for Blood DiseasesAlfred Hospital‐Monash UniversityMelbourneVICAustralia
| | - Andrew J Highton
- Department of Microbiology and ImmunologyUniversity of OtagoDunedinNew Zealand
| | | | - Jake Shortt
- Monash HaematologyMonash HealthClaytonVICAustralia
- Blood Cancer Therapeutics Laboratory, Department of MedicineSchool of Clinical Sciences at Monash HealthClaytonVICAustralia
| | - Andrew Spencer
- Myeloma Research Group, Australian Centre for Blood DiseasesAlfred Hospital‐Monash UniversityMelbourneVICAustralia
- Department of Clinical Haematology and Stem Cell TransplantationAlfred HospitalMelbourneVICAustralia
| | - Roslyn A Kemp
- Department of Microbiology and ImmunologyUniversity of OtagoDunedinNew Zealand
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15
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Sharma NS, Choudhary B. Good Cop, Bad Cop: Profiling the Immune Landscape in Multiple Myeloma. Biomolecules 2023; 13:1629. [PMID: 38002311 PMCID: PMC10669790 DOI: 10.3390/biom13111629] [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: 09/29/2023] [Revised: 10/26/2023] [Accepted: 10/29/2023] [Indexed: 11/26/2023] Open
Abstract
Multiple myeloma (MM) is a dyscrasia of plasma cells (PCs) characterized by abnormal immunoglobulin (Ig) production. The disease remains incurable due to a multitude of mutations and structural abnormalities in MM cells, coupled with a favorable microenvironment and immune suppression that eventually contribute to the development of drug resistance. The bone marrow microenvironment (BMME) is composed of a cellular component comprising stromal cells, endothelial cells, osteoclasts, osteoblasts, and immune cells, and a non-cellular component made of the extracellular matrix (ECM) and the liquid milieu, which contains cytokines, growth factors, and chemokines. The bone marrow stromal cells (BMSCs) are involved in the adhesion of MM cells, promote the growth, proliferation, invasion, and drug resistance of MM cells, and are also crucial in angiogenesis and the formation of lytic bone lesions. Classical immunophenotyping in combination with advanced immune profiling using single-cell sequencing technologies has enabled immune cell-specific gene expression analysis in MM to further elucidate the roles of specific immune cell fractions from peripheral blood and bone marrow (BM) in myelomagenesis and progression, immune evasion and exhaustion mechanisms, and development of drug resistance and relapse. The review describes the role of BMME components in MM development and ongoing clinical trials using immunotherapeutic approaches.
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Affiliation(s)
- Niyati Seshagiri Sharma
- Institute of Bioinformatics and Applied Biotechnology (IBAB), Electronic City, Bengaluru 560100, India
- Manipal Academy of Higher Education (MAHE), Manipal 576104, India
| | - Bibha Choudhary
- Institute of Bioinformatics and Applied Biotechnology (IBAB), Electronic City, Bengaluru 560100, India
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16
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Liu Z, Zhao X, Shen H, Liu X, Xu X, Fu R. Cellular immunity in the era of modern multiple myeloma therapy. Int J Cancer 2023; 153:1436-1447. [PMID: 37306091 DOI: 10.1002/ijc.34609] [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: 11/29/2022] [Revised: 03/24/2023] [Accepted: 04/03/2023] [Indexed: 06/13/2023]
Abstract
Multiple myeloma (MM) is a relapsing clonal plasma cell malignancy and incurable thus far. With the increasing understanding of myeloma, highlighting the critical importance of the immune system in the pathogenesis of MM is essential. The immune changes in MM patients after treatment are associated with prognosis. In this review, we summarize currently available MM therapies and discuss how they affect cellular immunity. We find that the modern anti-MM treatments enhance antitumour immune responses. A deeper understanding of the therapeutic activity of individual drugs offers more effective treatment approaches that enhance the beneficial immunomodulatory effects. Furthermore, we show that the immune changes after treatment in MM patients can provide useful prognostic marker. Analysing cellular immune responses offers new perspectives for evaluating clinical data and making comprehensive predictions for applying novel therapies in MM patients.
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Affiliation(s)
- Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, Heping District, Tianjin, China
| | - Xianghong Zhao
- Department of Hematology, Tianjin Medical University General Hospital, Heping District, Tianjin, China
| | - Hongli Shen
- Department of Hematology, Tianjin Medical University General Hospital, Heping District, Tianjin, China
| | - Xiaohan Liu
- Department of Hematology, Tianjin Medical University General Hospital, Heping District, Tianjin, China
| | - Xintong Xu
- Department of Hematology, Tianjin Medical University General Hospital, Heping District, Tianjin, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Heping District, Tianjin, China
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17
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Chen M, Jiang J, Hou J. Single-cell technologies in multiple myeloma: new insights into disease pathogenesis and translational implications. Biomark Res 2023; 11:55. [PMID: 37259170 PMCID: PMC10234006 DOI: 10.1186/s40364-023-00502-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 05/12/2023] [Indexed: 06/02/2023] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy characterized by clonal proliferation of plasma cells. Although therapeutic advances have been made to improve clinical outcomes and to prolong patients' survival in the past two decades, MM remains largely incurable. Single-cell sequencing (SCS) is a powerful method to dissect the cellular and molecular landscape at single-cell resolution, instead of providing averaged results. The application of single-cell technologies promises to address outstanding questions in myeloma biology and has revolutionized our understanding of the inter- and intra-tumor heterogeneity, tumor microenvironment, and mechanisms of therapeutic resistance in MM. In this review, we summarize the recently developed SCS methodologies and latest MM research progress achieved by single-cell profiling, including information regarding the cancer and immune cell landscapes, tumor heterogeneities, underlying mechanisms and biomarkers associated with therapeutic response and resistance. We also discuss future directions of applying transformative SCS approaches with contribution to clinical translation.
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Affiliation(s)
- Mengping Chen
- Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Jinxing Jiang
- Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Jian Hou
- Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
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18
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Improving NK cell function in multiple myeloma with NKTR-255, a novel polymer-conjugated human IL-15. Blood Adv 2023; 7:9-19. [PMID: 35882498 DOI: 10.1182/bloodadvances.2022007985] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/27/2022] [Accepted: 07/12/2022] [Indexed: 01/18/2023] Open
Abstract
Multiple myeloma (MM) is characterized by an immunosuppressive microenvironment that enables tumor development. One of the mechanisms of immune evasion used by MM cells is the inhibition of natural killer (NK) cell effector functions; thus, the restoration of NK cell antitumor activity represents a key goal to increase tumor cell recognition, avoid tumor escape and potentially enhancing the effect of other drugs. In this study, we evaluated the ability of the investigational medicine NKTR-255, an IL-15 receptor agonist, to engage the IL-15 pathway and stimulate NK cells against MM cells. We observed that incubation with NKTR-255 was able to tilt the balance toward an activated phenotype in NK cells isolated from peripheral blood mononuclear cells of patients with MM, with increased expression of activating receptors on the surface of treated NK cells. This resulted in an enhanced degranulation, cytokine release, and anti-tumor cytotoxicity when the NK cells were exposed to both MM cell lines and primary MM cells. We further evaluated the in vivo effect of NKTR-255 in fully humanized immunocompetent mice subcutaneously engrafted with H929 MM cells. Compared with placebo, weekly injection of the mice with NKTR-255 increased the number of circulating NK cells in peripheral blood and delayed tumor growth. Finally, we observed that combination of NKTR-255 with the anti-CD38 antibody, daratumumab, was effective against MM cells in vitro and in vivo. Taken together, our data suggest a significant impact of NKTR-255 in inducing NK cell function against MM cells with important translational implications.
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19
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Monoclonal Gammopathies and the Bone Marrow Microenvironment: From Bench to Bedside and Then Back Again. Hematol Rep 2023; 15:23-49. [PMID: 36648882 PMCID: PMC9844382 DOI: 10.3390/hematolrep15010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 09/11/2022] [Accepted: 01/03/2023] [Indexed: 01/12/2023] Open
Abstract
Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called "smoldering" MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients' survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities.
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20
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Wang SSY, Chng WJ, Liu H, de Mel S. Tumor-Associated Macrophages and Related Myelomonocytic Cells in the Tumor Microenvironment of Multiple Myeloma. Cancers (Basel) 2022; 14:5654. [PMID: 36428745 PMCID: PMC9688291 DOI: 10.3390/cancers14225654] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/05/2022] [Accepted: 11/11/2022] [Indexed: 11/19/2022] Open
Abstract
Multiple myeloma (MM) is the second-most common hematologic malignancy and remains incurable despite potent plasma cell directed therapeutics. The tumor microenvironment (TME) is a key player in the pathogenesis and progression of MM and is an active focus of research with a view to targeting immune dysregulation. Tumor-associated macrophages (TAM), myeloid derived suppressor cells (MDSC), and dendritic cells (DC) are known to drive progression and treatment resistance in many cancers. They have also been shown to promote MM progression and immune suppression in vitro, and there is growing evidence of their impact on clinical outcomes. The heterogeneity and functional characteristics of myelomonocytic cells in MM are being unraveled through high-dimensional immune profiling techniques. We are also beginning to understand how they may affect and be modulated by current and future MM therapeutics. In this review, we provide an overview of the biology and clinical relevance of TAMs, MDSCs, and DCs in the MM TME. We also highlight key areas to be addressed in future research as well as our perspectives on how the myelomonocytic compartment of the TME may influence therapeutic strategies of the future.
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Affiliation(s)
- Samuel S. Y. Wang
- Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Wee Joo Chng
- Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore 119228, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597, Singapore
- Cancer Science Institute, National University of Singapore, 14 Medical Dr, #12-01 Centre for Translational Medicine, Singapore 117599, Singapore
| | - Haiyan Liu
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore
- Immunology Translational Research Program, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Sanjay de Mel
- Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore 119228, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597, Singapore
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21
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Boussi LS, Avigan ZM, Rosenblatt J. Immunotherapy for the treatment of multiple myeloma. Front Immunol 2022; 13:1027385. [PMID: 36389674 PMCID: PMC9649817 DOI: 10.3389/fimmu.2022.1027385] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/12/2022] [Indexed: 12/05/2022] Open
Abstract
Despite advances in treatment for multiple myeloma, the majority of patients ultimately develop relapsed disease marked by immune evasion and resistance to standard therapy. Immunotherapy has emerged as a powerful tool for tumor-directed cytotoxicity with the unique potential to induce immune memory to reduce the risk of relapse. Understanding the specific mechanisms of immune dysregulation and dysfunction in advanced myeloma is critical to the development of further therapies that produce a durable response. Adoptive cellular therapy, most strikingly CAR T cell therapy, has demonstrated dramatic responses in the setting of refractory disease. Understanding the factors that contribute to immune evasion and the mechanisms of response and resistance to therapy will be critical to developing the next generation of adoptive cellular therapies, informing novel combination therapy, and determining the optimal time to incorporate immune therapy in the treatment of myeloma.
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Affiliation(s)
- Leora S. Boussi
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Zachary M. Avigan
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Jacalyn Rosenblatt
- Division of Hematology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
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22
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Dendritic Cells: The Long and Evolving Road towards Successful Targetability in Cancer. Cells 2022; 11:cells11193028. [PMID: 36230990 PMCID: PMC9563837 DOI: 10.3390/cells11193028] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/19/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Dendritic cells (DCs) are a unique myeloid cell lineage that play a central role in the priming of the adaptive immune response. As such, they are an attractive target for immune oncology based therapeutic approaches. However, targeting these cells has proven challenging with many studies proving inconclusive or of no benefit in a clinical trial setting. In this review, we highlight the known and unknown about this rare but powerful immune cell. As technologies have expanded our understanding of the complexity of DC development, subsets and response features, we are now left to apply this knowledge to the design of new therapeutic strategies in cancer. We propose that utilization of these technologies through a multiomics approach will allow for an improved directed targeting of DCs in a clinical trial setting. In addition, the DC research community should consider a consensus on subset nomenclature to distinguish new subsets from functional or phenotypic changes in response to their environment.
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23
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Soekojo CY, Chng WJ. The Evolution Of Immune Dysfunction In Multiple Myeloma. Eur J Haematol 2022; 109:415-424. [PMID: 35880386 DOI: 10.1111/ejh.13839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 07/23/2022] [Indexed: 11/28/2022]
Abstract
OBJECTIVES This review discusses the role of immune dysfunction at the different stages of MM. METHODS Narrative review RESULTS: Multiple myeloma (MM) is a complex disease and immune dysfunction has been known to play an important role in disease pathogenesis, progression, and drug resistance. MM is known to be preceded by asymptomatic precursor states and progression from the precursor states to MM is likely related to a progressive impairment of the immune system. CONCLUSIONS An understanding of the role of the immune system in the progression of MM is important to guide the development of immunotherapeutic strategies for this disease.
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Affiliation(s)
- Cinnie Yentia Soekojo
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, National University Health System
| | - Wee Joo Chng
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, National University Health System
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24
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Chu TH, Vo MC, Lakshmi TJ, Ahn SY, Kim M, Song GY, Yang DH, Ahn JS, Kim HJ, Jung SH, Lee JJ. Novel IL-15 dendritic cells have a potent immunomodulatory effect in immunotherapy of multiple myeloma. Transl Oncol 2022; 20:101413. [PMID: 35413499 PMCID: PMC9006865 DOI: 10.1016/j.tranon.2022.101413] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Culture DCs with GM-CSF + IL-4 + IL-15 (IL-15 DCs) can be shortened for 6 days. IL-15 DCs showed high expression levels of costimulatory receptors, IFN-γ and IL-12p70. IL-15 DCs showed strong stimulation toward T, CIK and NK cells. The activated lymphocytes showed high cytotoxicity against myeloma cells. Dendritic cells (DCs) are the most potent antigen-presenting cells, and have thus been used in clinical cancer vaccines. However, the effects of DC vaccines are still limited, leading researchers to explore novel ways to make them effective. In this study, we investigated whether human monocyte-derived DCs generated via the addition of interleukin 15 (IL-15) had a higher capacity to induce antigen-specific T cells compared to conventional DCs. We isolated CD14+ monocytes from peripheral blood from multiple myeloma (MM) patients, and induced immature DCs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 in the presence or absence of IL-15 for 4–6 days. Then we generated mature DCs (mDCs) with lipopolysaccharide for another 2 days [IL-15 mDCs (6 days), IL-15 mDCs (8 days), and conventional mDCs (8 days)]. IL-15 mDCs (6 days) showed higher expression of MHC I and II, CD40, CD86, and CCR7, and the secretion of IFN-γ was significantly higher compared to conventional mDCs. IL-15 mDCs (6 days) showed superior polarization of naïve T cells toward Th1 cells and a higher proportion of activated T cells, cytokine-induced killer (CIK) cells, and natural killer (NK) cells for inducing strong cytotoxicity against myeloma cells, and lower proportion of regulatory T cells compared to conventional mDCs. These data imply that novel multipotent mDCs generated by the addition of IL-15, which can be cultivated in 6 days, resulted in outstanding activation of T cells, CIK cells and NK cells, and may facilitate cellular immunotherapy for cancer patients.
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25
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Chu J, Gao F, Yan M, Zhao S, Yan Z, Shi B, Liu Y. Natural killer cells: a promising immunotherapy for cancer. J Transl Med 2022; 20:240. [PMID: 35606854 PMCID: PMC9125849 DOI: 10.1186/s12967-022-03437-0] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 05/12/2022] [Indexed: 12/14/2022] Open
Abstract
As a promising alternative platform for cellular immunotherapy, natural killer cells (NK) have recently gained attention as an important type of innate immune regulatory cell. NK cells can rapidly kill multiple adjacent cancer cells through non-MHC-restrictive effects. Although tumors may develop multiple resistance mechanisms to endogenous NK cell attack, in vitro activation, expansion, and genetic modification of NK cells can greatly enhance their anti-tumor activity and give them the ability to overcome drug resistance. Some of these approaches have been translated into clinical applications, and clinical trials of NK cell infusion in patients with hematological malignancies and solid tumors have thus far yielded many encouraging clinical results. CAR-T cells have exhibited great success in treating hematological malignancies, but their drawbacks include high manufacturing costs and potentially fatal toxicity, such as cytokine release syndrome. To overcome these issues, CAR-NK cells were generated through genetic engineering and demonstrated significant clinical responses and lower adverse effects compared with CAR-T cell therapy. In this review, we summarize recent advances in NK cell immunotherapy, focusing on NK cell biology and function, the types of NK cell therapy, and clinical trials and future perspectives on NK cell therapy.
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Affiliation(s)
- Junfeng Chu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, Henan, China
| | - Fengcai Gao
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Meimei Yan
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, Henan, China
| | - Shuang Zhao
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, Henan, China
| | - Zheng Yan
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, Henan, China
| | - Bian Shi
- Department of Chinese and Western Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, Henan, China.
| | - Yanyan Liu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, Henan, China.
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Ohmine K, Uchibori R. Novel immunotherapies in multiple myeloma. Int J Hematol 2022; 115:799-810. [PMID: 35583724 DOI: 10.1007/s12185-022-03365-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 04/18/2022] [Accepted: 04/19/2022] [Indexed: 11/24/2022]
Abstract
For a substantial period, options for the treatment of multiple myeloma (MM) were limited; however, the advent of novel therapies into clinical practice in the 1990s resulted in dramatic changes in the prognosis of the disease. Subsequently, new proteasome inhibitors and immunomodulators with innovations in efficacy and toxicity were introduced; yet there remains a spectrum of patients with poor outcomes with current treatment strategies. One of the causes of disease progression in MM is the loss of the ability of the dysfunctional immune environment to control virulent cell clones. In recent years, therapies to overcome the immunosuppressive tumor microenvironment and activate the host immune system have shown promise in MM, especially in relapsed and refractory disease. Clinical use of this approach has been approved for several immunotherapies, and a number of studies are currently underway in clinical trials. This review outlines three of the newest and most promising approaches being investigated to enhance the immune system against MM: (1) overcoming immunosuppression with checkpoint inhibitors, (2) boosting immunity against tumors with vaccines, and (3) enhancing immune effectors with adoptive cell therapy. Information on the latest clinical trials in each class will be provided, and further developments will be discussed.
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Affiliation(s)
- Ken Ohmine
- Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
- Division of Immuno-Gene and Cell Therapy (Takara Bio), Jichi Medical University, Shimotsuke, Tochigi, Japan.
| | - Ryosuke Uchibori
- Division of Immuno-Gene and Cell Therapy (Takara Bio), Jichi Medical University, Shimotsuke, Tochigi, Japan
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Dendritic cell-based cancer immunotherapy in the era of immune checkpoint inhibitors: From bench to bedside. Life Sci 2022; 297:120466. [PMID: 35271882 DOI: 10.1016/j.lfs.2022.120466] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/02/2022] [Accepted: 03/04/2022] [Indexed: 12/18/2022]
Abstract
Dendritic cells (DCs) can present tumoral antigens to T-cells and stimulate T-cell-mediated anti-tumoral immune responses. In addition to uptaking, processing, and presenting tumoral antigens to T-cells, co-stimulatory signals have to be established between DCs with T-cells to develop anti-tumoral immune responses. However, most of the tumor-infiltrated immune cells are immunosuppressive in the tumor microenvironment (TME), paving the way for immune evasion of tumor cells. This immunosuppressive TME has also been implicated in suppressing the DC-mediated anti-tumoral immune responses, as well. Various factors, i.e., immunoregulatory cells, metabolic factors, tumor-derived immunosuppressive factors, and inhibitory immune checkpoint molecules, have been implicated in developing the immunosuppressive TME. Herein, we aimed to review the biology of DCs in developing T-cell-mediated anti-tumoral immune responses, the significance of immunoregulatory cells in the TME, metabolic barriers contributing to DCs dysfunction in the TME, tumor-derived immunosuppressive factors, and inhibitory immune checkpoint molecules in DC-based cell therapy outcomes. With reviewing the ongoing clinical trials, we also proposed a novel therapeutic strategy to increase the efficacy of DC-based cell therapy. Indeed, the combination of DC-based cell therapy with monoclonal antibodies against novel immune checkpoint molecules can be a promising strategy to increase the response rate of patients with cancers.
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Swamydas M, Murphy EV, Ignatz-Hoover JJ, Malek E, Driscoll JJ. Deciphering mechanisms of immune escape to inform immunotherapeutic strategies in multiple myeloma. J Hematol Oncol 2022; 15:17. [PMID: 35172851 PMCID: PMC8848665 DOI: 10.1186/s13045-022-01234-2] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/03/2022] [Indexed: 12/11/2022] Open
Abstract
Multiple myeloma is an incurable cancer characterized by the uncontrolled growth of malignant plasma cells nurtured within a permissive bone marrow microenvironment. While patients mount numerous adaptive immune responses directed against their disease, emerging data demonstrate that tumor intrinsic and extrinsic mechanisms allow myeloma cells to subvert host immunosurveillance and resist current therapeutic strategies. Myeloma downregulates antigens recognized by cellular immunity and modulates the bone marrow microenvironment to promote uncontrolled tumor proliferation, apoptotic resistance, and further hamper anti-tumor immunity. Additional resistance often develops after an initial clinical response to small molecules, immune-targeting antibodies, immune checkpoint blockade or cellular immunotherapy. Profound quantitative and qualitative dysfunction of numerous immune effector cell types that confer anti-myeloma immunity further supports myelomagenesis, disease progression and the emergence of drug resistance. Identification of tumor intrinsic and extrinsic resistance mechanisms may direct the design of rationally-designed drug combinations that prevent or overcome drug resistance to improve patient survival. Here, we summarize various mechanisms of immune escape as a means to inform novel strategies that may restore and improve host anti-myeloma immunity.
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Affiliation(s)
| | - Elena V Murphy
- Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA
| | - James J Ignatz-Hoover
- Seidman Cancer Center, University Hospitals, Cleveland, OH, USA.,Case Comprehensive Cancer Center, Hematopoietic and Immune Cancer Biology Program, Cleveland, OH, USA
| | - Ehsan Malek
- Seidman Cancer Center, University Hospitals, Cleveland, OH, USA.,Case Comprehensive Cancer Center, Hematopoietic and Immune Cancer Biology Program, Cleveland, OH, USA
| | - James J Driscoll
- Seidman Cancer Center, University Hospitals, Cleveland, OH, USA. .,Case Comprehensive Cancer Center, Hematopoietic and Immune Cancer Biology Program, Cleveland, OH, USA.
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Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. Lancet Haematol 2022; 9:e143-e161. [DOI: 10.1016/s2352-3026(21)00283-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/26/2021] [Accepted: 09/07/2021] [Indexed: 12/14/2022]
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Langerhans dendritic cell vaccines bearing mRNA-encoded tumor antigens induce anti-myeloma immunity after autotransplant. Blood Adv 2022; 6:1547-1558. [PMID: 35100339 PMCID: PMC8905697 DOI: 10.1182/bloodadvances.2021005941] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 01/03/2022] [Indexed: 11/20/2022] Open
Abstract
Triple antigen–bearing mRNA-electroporated autologous LC vaccines after ASCT for MM are safe and immunogenic. Posttransplant vaccination targeting residual disease is an immunotherapeutic strategy to improve antigen-specific immune responses and prolong disease-free survival after autologous stem cell transplantation (ASCT) for multiple myeloma (MM). We conducted a phase 1 vaccine trial to determine the safety, toxicity, and immunogenicity of autologous Langerhans-type dendritic cells (LCs) electroporated with CT7, MAGE-A3, and Wilms tumor 1 (WT1) messenger RNA (mRNA), after ASCT for MM. Ten patients received a priming immunization plus 2 boosters at 12, 30, and 90 days, respectively, after ASCT. Vaccines contained 9 × 106 mRNA-electroporated LCs. Ten additional patients did not receive LC vaccines but otherwise underwent identical ASCT and supportive care. At 3 months after ASCT, all patients started lenalidomide maintenance therapy. Vaccinated patients developed mild local delayed-type hypersensitivity reactions after booster vaccines, but no toxicities exceeded grade 1. At 1 and 3 months after vaccines, antigen-specific CD4 and CD8 T cells increased secretion of proinflammatory cytokines (interferon-γ, interleukin-2, and tumor necrosis factor-α) above prevaccine levels, and also upregulated the cytotoxicity marker CD107a. CD4 and CD8 T-cell repertoire analysis showed a trend for increased clonal expansion in the vaccine cohort, which was more pronounced in the CD4 compartment. Although not powered to assess clinical efficacy, treatment responses favored the vaccine arm. Triple antigen–bearing mRNA-electroporated autologous LC vaccination initiated at engraftment after ASCT, in conjunction with standard lenalidomide maintenance therapy for MM, is safe and induces antigen-specific immune reactivity. This trial was registered at www.clinicaltrials.gov as #NCT01995708.
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Verheye E, Bravo Melgar J, Deschoemaeker S, Raes G, Maes A, De Bruyne E, Menu E, Vanderkerken K, Laoui D, De Veirman K. Dendritic Cell-Based Immunotherapy in Multiple Myeloma: Challenges, Opportunities, and Future Directions. Int J Mol Sci 2022; 23:904. [PMID: 35055096 PMCID: PMC8778019 DOI: 10.3390/ijms23020904] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/11/2022] [Indexed: 12/12/2022] Open
Abstract
Immunotherapeutic approaches, including adoptive cell therapy, revolutionized treatment in multiple myeloma (MM). As dendritic cells (DCs) are professional antigen-presenting cells and key initiators of tumor-specific immune responses, DC-based immunotherapy represents an attractive therapeutic approach in cancer. The past years, various DC-based approaches, using particularly ex-vivo-generated monocyte-derived DCs, have been tested in preclinical and clinical MM studies. However, long-term and durable responses in MM patients were limited, potentially attributed to the source of monocyte-derived DCs and the immunosuppressive bone marrow microenvironment. In this review, we briefly summarize the DC development in the bone marrow niche and the phenotypical and functional characteristics of the major DC subsets. We address the known DC deficiencies in MM and give an overview of the DC-based vaccination protocols that were tested in MM patients. Lastly, we also provide strategies to improve the efficacy of DC vaccines using new, improved DC-based approaches and combination therapies for MM patients.
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Affiliation(s)
- Emma Verheye
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium; (J.B.M.); (S.D.); (G.R.)
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Jesús Bravo Melgar
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium; (J.B.M.); (S.D.); (G.R.)
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Sofie Deschoemaeker
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium; (J.B.M.); (S.D.); (G.R.)
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Geert Raes
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium; (J.B.M.); (S.D.); (G.R.)
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Anke Maes
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
| | - Elke De Bruyne
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
| | - Eline Menu
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
| | - Karin Vanderkerken
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
| | - Damya Laoui
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium; (J.B.M.); (S.D.); (G.R.)
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Kim De Veirman
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
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Subtil B, Cambi A, Tauriello DVF, de Vries IJM. The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer. Front Immunol 2021; 12:724883. [PMID: 34691029 PMCID: PMC8527179 DOI: 10.3389/fimmu.2021.724883] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME.
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Affiliation(s)
- Beatriz Subtil
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alessandra Cambi
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Daniele V. F. Tauriello
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - I. Jolanda M. de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
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Abstract
Dendritic cells (DCs) are efficient antigen-presenting cells that serve as a link between the innate and adaptive immune systems. These cells are broadly involved in cellular and humoral immune responses by presenting antigens to initiate T cell reactions, cytokine and chemokine secretion, T cell differentiation and expansion, B cell activation and regulation, and the mediation of immune tolerance. The functions of DCs depend on their activation status, which is defined by the stages of maturation, phenotype differentiation, and migration ability, among other factors. IL-6 is a soluble mediator mainly produced by a variety of immune cells, including DCs, that exerts pleiotropic effects on immune and inflammatory responses through interaction with specific receptors expressed on the surface of target cells. Here, we review the role of IL-6, when generated in an inflammatory context or as derived from DCs, in modulating the biologic function and activation status of DCs and emphasize the importance of searching for novel strategies to target the IL-6/IL-6 signaling pathway as a means to diminish the inflammatory activity of DCs in immune response or to prime the immunogenic activity of DCs in immunosuppressive conditions.
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Affiliation(s)
- Yu-Dong Xu
- Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mi Cheng
- Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Pan-Pan Shang
- Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong-Qing Yang
- Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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34
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Ludwig H, San‐Miguel J, Munshi N, Sonneveld P, Mateos M, Moreau P, Terpos E. Covid-19 vaccination in patients with multiple myeloma: Focus on immune response. Am J Hematol 2021; 96:896-900. [PMID: 34057243 PMCID: PMC8212086 DOI: 10.1002/ajh.26263] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 05/12/2021] [Indexed: 12/31/2022]
Affiliation(s)
- Heinz Ludwig
- First Department of Medicine, Clinic OttakringWilhelminen Cancer Research InstituteViennaAustria
| | - Jesús San‐Miguel
- CIMA, IDISNA, CIBERONC, Clínica Universidad de NavarraPamplonaSpain
| | - Nikhil Munshi
- Jerome Lipper Multiple Myeloma Center, Dana‐Farber Cancer Institute, Harvard Medical SchoolBostonMassachusettsUSA
| | - Pieter Sonneveld
- Erasmus MC Cancer Institute, Erasmus University of RotterdamRotterdamThe Netherlands
| | | | - Philippe Moreau
- Department of HematologyUniversity Hospital NantesNantesFrance
| | - Evangelos Terpos
- Hematology & Medical Oncology, Department of Clinical TherapeuticsNational and Kapodistrian University of AthensAthensGreece
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35
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Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther 2021; 6:263. [PMID: 34248142 PMCID: PMC8273155 DOI: 10.1038/s41392-021-00658-5] [Citation(s) in RCA: 1257] [Impact Index Per Article: 314.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 05/11/2021] [Accepted: 05/23/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.
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36
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Patnaik MM, Mughal TI, Brooks C, Lindsay R, Pemmaraju N. Targeting CD123 in hematologic malignancies: identifying suitable patients for targeted therapy. Leuk Lymphoma 2021; 62:2568-2586. [PMID: 33999767 DOI: 10.1080/10428194.2021.1927021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Following the observation of interleukin 3 receptor α chain (IL-3Rα; CD123) upregulation on leukemia stem cells (LSCs) almost two decades ago, targeted treatment via CD123-diptheria toxin conjugates has now been tested in patients with diverse myeloid malignancies. Targeted eradication of LSCs could result in effective treatments for many challenging diseases initiated by these cells. Consequently, considerable effort has been directed toward targeting CD123 as a potential strategy for treating patients with hematologic malignancies in which CD123 is overexpressed. However, these therapies have had limited success so far, highlighting the need for suitable criteria to identify patients who could benefit from them. Given the diversity in CD123 expression across different hematologic malignancies, understanding CD123 expression patterns and the functional pathogenetic significance is crucial. Here, we review the methodologies available for CD123 assessment and discuss the biological and clinical characteristics of patients for whom CD123-targeting therapies may have a clinical impact.
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Affiliation(s)
- Mrinal M Patnaik
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Tariq I Mughal
- Division of Hematology-Oncology, Tufts University School of Medicine, Boston, MA, USA.,Research & Clinical Drug Development, Stemline Therapeutics, New York, NY, USA
| | - Christopher Brooks
- Research & Clinical Drug Development, Stemline Therapeutics, New York, NY, USA
| | - Ross Lindsay
- Research & Clinical Drug Development, Stemline Therapeutics, New York, NY, USA
| | - Naveen Pemmaraju
- Division of Cancer Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses. Blood Adv 2021; 4:3572-3585. [PMID: 32761232 DOI: 10.1182/bloodadvances.2019001410] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 05/01/2020] [Indexed: 11/20/2022] Open
Abstract
Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, are widely used treatments for multiple myeloma; however, they occasionally lead to episodes of itchy skin and rashes. Here, we analyzed the effects of IMiDs on human myeloid dendritic cells (mDCs) as major regulators of Th1 or Th2 responses and the role they play in allergy. We found that lenalidomide and pomalidomide used at clinical concentrations did not affect the survival or CD86 and OX40-ligand expression of blood mDCs in response to lipopolysaccharide (LPS) and thymic stromal lymphopoietin (TSLP) stimulation. Both lenalidomide and pomalidomide dose-dependently inhibited interleukin-12 (IL-12) and TNF production and STAT4 expression, and enhanced IL-10 production in response to LPS. When stimulated with TSLP, both IMiDs significantly enhanced CCL17 production and STAT6 and IRF4 expression and promoted memory Th2-cell responses. In 46 myeloma patients, serum CCL17 levels at the onset of lenalidomide-associated rash were significantly higher than those without rashes during lenalidomide treatment and those before treatment. Furthermore, serum CCL17 levels in patients who achieved a very good partial response (VGPR) were significantly higher compared with a less than VGPR during lenalidomide treatment. The median time to next treatment was significantly longer in lenalidomide-treated patients with rashes than those without. Collectively, IMiDs suppressed the Th1-inducing capacity of DCs, instead promoting a Th2 response. Thus, the lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation.
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Giannakoulas N, Ntanasis-Stathopoulos I, Terpos E. The Role of Marrow Microenvironment in the Growth and Development of Malignant Plasma Cells in Multiple Myeloma. Int J Mol Sci 2021; 22:ijms22094462. [PMID: 33923357 PMCID: PMC8123209 DOI: 10.3390/ijms22094462] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 12/16/2022] Open
Abstract
The development and effectiveness of novel therapies in multiple myeloma have been established in large clinical trials. However, multiple myeloma remains an incurable malignancy despite significant therapeutic advances. Accumulating data have elucidated our understanding of the genetic background of the malignant plasma cells along with the role of the bone marrow microenvironment. Currently, the interaction among myeloma cells and the components of the microenvironment are considered crucial in multiple myeloma pathogenesis. Adhesion molecules, cytokines and the extracellular matrix play a critical role in the interplay among genetically transformed clonal plasma cells and stromal cells, leading to the proliferation, progression and survival of myeloma cells. In this review, we provide an overview of the multifaceted role of the bone marrow microenvironment in the growth and development of malignant plasma cells in multiple myeloma.
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Affiliation(s)
- Nikolaos Giannakoulas
- Department of Hematology of University Hospital of Larisa, Faculty of Medicine, University of Thessaly, 41110 Larisa, Greece;
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Evangelos Terpos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece;
- Correspondence:
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Thapsigargin-Stimulated LAD2 Human Mast Cell Line Is a Potent Cellular Adjuvant for the Maturation of Monocyte-Derived Dendritic Cells for Adoptive Cellular Immunotherapy. Int J Mol Sci 2021; 22:ijms22083978. [PMID: 33921475 PMCID: PMC8069665 DOI: 10.3390/ijms22083978] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/23/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022] Open
Abstract
The preparation of dendritic cells (DCs) for adoptive cellular immunotherapy (ACI) requires the maturation of ex vivo-produced immature(i) DCs. This maturation ensures that the antigen presentation triggers an immune response towards the antigen-expressing cells. Although there is a large number of maturation agents capable of inducing strong DC maturation, there is still only a very limited number of these agents approved for use in the production of DCs for ACI. In seeking novel DC maturation agents, we used differentially activated human mast cell (MC) line LAD2 as a cellular adjuvant to elicit or modulate the maturation of ex vivo-produced monocyte-derived iDCs. We found that co-culture of iDCs with differentially activated LAD2 MCs in serum-containing media significantly modulated polyinosinic:polycytidylic acid (poly I:C)-elicited DC maturation as determined through the surface expression of the maturation markers CD80, CD83, CD86, and human leukocyte antigen(HLA)-DR. Once iDCs were generated in serum-free conditions, they became refractory to the maturation with poly I:C, and the LAD2 MC modulatory potential was minimized. However, the maturation-refractory phenotype of the serum-free generated iDCs was largely overcome by co-culture with thapsigargin-stimulated LAD2 MCs. Our data suggest that differentially stimulated mast cells could be novel and highly potent cellular adjuvants for the maturation of DCs for ACI.
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Damasceno D, Almeida J, Teodosio C, Sanoja-Flores L, Mayado A, Pérez-Pons A, Puig N, Arana P, Paiva B, Solano F, Romero A, Matarraz S, van den Bossche WBL, Flores-Montero J, Durie B, van Dongen JJM, Orfao A. Monocyte Subsets and Serum Inflammatory and Bone-Associated Markers in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma. Cancers (Basel) 2021; 13:cancers13061454. [PMID: 33810169 PMCID: PMC8004952 DOI: 10.3390/cancers13061454] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/16/2021] [Accepted: 03/18/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Monocyte/macrophages have been shown to be altered in monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), with an impact on the disruption of the homeostasis of the normal bone marrow (BM) microenvironment. METHODS We investigated the distribution of different subsets of monocytes (Mo) in blood and BM of newly-diagnosed untreated MGUS (n = 23), SMM (n = 14) and MM (n = 99) patients vs. healthy donors (HD; n = 107), in parallel to a large panel of cytokines and bone-associated serum biomarkers. RESULTS Our results showed normal production of monocyte precursors and classical Mo (cMo) in MGUS, while decreased in SMM and MM (p ≤ 0.02), in association with lower blood counts of recently-produced CD62L+ cMo in SMM (p = 0.004) and of all subsets of (CD62L+, CD62L- and FcεRI+) cMo in MM (p ≤ 0.02). In contrast, intermediate and end-stage non-classical Mo were increased in BM of MGUS (p ≤ 0.03), SMM (p ≤ 0.03) and MM (p ≤ 0.002), while normal (MGUS and SMM) or decreased (MM; p = 0.01) in blood. In parallel, increased serum levels of interleukin (IL)1β were observed in MGUS (p = 0.007) and SMM (p = 0.01), higher concentrations of serum IL8 were found in SMM (p = 0.01) and MM (p = 0.002), and higher serum IL6 (p = 0.002), RANKL (p = 0.01) and bone alkaline phosphatase (BALP) levels (p = 0.01) with decreased counts of FcεRI+ cMo, were restricted to MM presenting with osteolytic lesions. This translated into three distinct immune/bone profiles: (1) normal (typical of HD and most MGUS cases); (2) senescent-like (increased IL1β and/or IL8, found in a minority of MGUS, most SMM and few MM cases with no bone lesions); and (3) pro-inflammatory-high serum IL6, RANKL and BALP with significantly (p = 0.01) decreased blood counts of immunomodulatory FcεRI+ cMo-, typical of MM presenting with bone lesions. CONCLUSIONS These results provide new insight into the pathogenesis of plasma cell neoplasms and the potential role of FcεRI+ cMo in normal bone homeostasis.
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Affiliation(s)
- Daniela Damasceno
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (D.D.); (J.A.); (A.M.); (A.P.-P.); (S.M.); (J.F.-M.)
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain; (L.S.-F.); (N.P.); (B.P.)
| | - Julia Almeida
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (D.D.); (J.A.); (A.M.); (A.P.-P.); (S.M.); (J.F.-M.)
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain; (L.S.-F.); (N.P.); (B.P.)
| | - Cristina Teodosio
- Leiden University Medical Center, Department of Immunology, 2333 ZA Leiden, The Netherlands; (C.T.); (W.B.L.v.d.B.); (J.J.M.v.D.)
| | - Luzalba Sanoja-Flores
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain; (L.S.-F.); (N.P.); (B.P.)
- Institute of Biomedicine of Seville, Department of Hematology, University Hospital Virgen del Rocío of the Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, 41013 Seville, Spain
| | - Andrea Mayado
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (D.D.); (J.A.); (A.M.); (A.P.-P.); (S.M.); (J.F.-M.)
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain; (L.S.-F.); (N.P.); (B.P.)
| | - Alba Pérez-Pons
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (D.D.); (J.A.); (A.M.); (A.P.-P.); (S.M.); (J.F.-M.)
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain; (L.S.-F.); (N.P.); (B.P.)
| | - Noemi Puig
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain; (L.S.-F.); (N.P.); (B.P.)
- Service of Hematology, University Hospital of Salamanca (CAUSA) and IBSAL, 37007 Salamanca, Spain
| | - Paula Arana
- Regulation of the Immune System Group, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Plaza de Cruces 12, 48903 Barakaldo, Spain;
| | - Bruno Paiva
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain; (L.S.-F.); (N.P.); (B.P.)
- Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), Clinica Universidad de Navarra, 31008 Pamplona, Spain
| | - Fernando Solano
- Hematology Service, Hospital Nuestra Señora del Prado, Talavera de la Reina, 45600 Toledo, Spain;
| | - Alfonso Romero
- Primary Health Care Center “Miguel Armijo”, Primary Health Care of Salamanca, Conserjería de Sanidad de Castilla y León (SACYL), 37007 Salamanca, Spain;
| | - Sergio Matarraz
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (D.D.); (J.A.); (A.M.); (A.P.-P.); (S.M.); (J.F.-M.)
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain; (L.S.-F.); (N.P.); (B.P.)
| | - Wouter B. L. van den Bossche
- Leiden University Medical Center, Department of Immunology, 2333 ZA Leiden, The Netherlands; (C.T.); (W.B.L.v.d.B.); (J.J.M.v.D.)
- Department of Immunology, Erasmus University Medical Center, 3015 GA Rotterdam, The Netherlands
| | - Juan Flores-Montero
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (D.D.); (J.A.); (A.M.); (A.P.-P.); (S.M.); (J.F.-M.)
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain; (L.S.-F.); (N.P.); (B.P.)
| | - Brian Durie
- Centro del Cáncer Cedars-Sinai Samuel Oschin, Los Angeles, CA 90048, USA;
| | - Jacques J. M. van Dongen
- Leiden University Medical Center, Department of Immunology, 2333 ZA Leiden, The Netherlands; (C.T.); (W.B.L.v.d.B.); (J.J.M.v.D.)
| | - Alberto Orfao
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; (D.D.); (J.A.); (A.M.); (A.P.-P.); (S.M.); (J.F.-M.)
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain; (L.S.-F.); (N.P.); (B.P.)
- Correspondence:
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Díaz-Tejedor A, Lorenzo-Mohamed M, Puig N, García-Sanz R, Mateos MV, Garayoa M, Paíno T. Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression. Cancers (Basel) 2021; 13:cancers13061353. [PMID: 33802806 PMCID: PMC8002455 DOI: 10.3390/cancers13061353] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/14/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary A common characteristic of multiple myeloma (MM) is the dysfunction of patients’ immune system, a condition termed immunosuppression. This state is mainly due to alterations in the number and functionality of the principal immune populations. In this setting, immunotherapy has acquired high relevance in the last years and the investigation of agents that boost the immune system represent a field of interest. In the present review, we will summarize the main cellular and molecular alterations observed in MM patients’ immune system. Furthermore, we will describe the mechanisms of action of the four immunotherapeutic drugs approved so far for the treatment of MM, which are part of the group of monoclonal antibodies (mAbs). Finally, the immune-stimulating effects of several therapeutic agents are described due to their potential role in reversing immunosuppression and, therefore, in favoring the efficacy of immunotherapy drugs, such as mAbs, as part of future pharmacological combinations. Abstract Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterations in the expression of surface molecules are also responsible for immunosuppression. In this scenario, immunotherapy, as is the case of immunotherapeutic monoclonal antibodies (mAbs), aims to boost the immune system against tumor cells. In fact, mAbs exert part of their cytotoxic effects through different cellular and soluble immune components and, therefore, patients’ immunosuppressive status could reduce their efficacy. Here, we will expose the alterations observed in symptomatic MM, as compared to its precursor stages and healthy subjects, in the main immune populations, especially the inhibition of effector cells and the activation of immunosuppressive populations. Additionally, we will revise the mechanisms responsible for all these alterations, including the interplay between MM cells and immune cells and the interactions among immune cells themselves. We will also summarize the main mechanisms of action of the four mAbs approved so far for the treatment of MM. Finally, we will discuss the potential immune-stimulating effects of non-immunotherapeutic drugs, which could enhance the efficacy of immunotherapeutic treatments.
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Affiliation(s)
- Andrea Díaz-Tejedor
- Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Complejo Asistencial Universitario de Salamanca-IBSAL, Department of Hematology, 37007 Salamanca, Spain; (A.D.-T.); (M.L.-M.); (N.P.); (R.G.-S.); (M.-V.M.); (M.G.)
| | - Mauro Lorenzo-Mohamed
- Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Complejo Asistencial Universitario de Salamanca-IBSAL, Department of Hematology, 37007 Salamanca, Spain; (A.D.-T.); (M.L.-M.); (N.P.); (R.G.-S.); (M.-V.M.); (M.G.)
| | - Noemí Puig
- Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Complejo Asistencial Universitario de Salamanca-IBSAL, Department of Hematology, 37007 Salamanca, Spain; (A.D.-T.); (M.L.-M.); (N.P.); (R.G.-S.); (M.-V.M.); (M.G.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, CB16/12/00233), Instituto de Salud Carlos III, 37007 Salamanca, Spain
| | - Ramón García-Sanz
- Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Complejo Asistencial Universitario de Salamanca-IBSAL, Department of Hematology, 37007 Salamanca, Spain; (A.D.-T.); (M.L.-M.); (N.P.); (R.G.-S.); (M.-V.M.); (M.G.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, CB16/12/00233), Instituto de Salud Carlos III, 37007 Salamanca, Spain
| | - María-Victoria Mateos
- Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Complejo Asistencial Universitario de Salamanca-IBSAL, Department of Hematology, 37007 Salamanca, Spain; (A.D.-T.); (M.L.-M.); (N.P.); (R.G.-S.); (M.-V.M.); (M.G.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, CB16/12/00233), Instituto de Salud Carlos III, 37007 Salamanca, Spain
| | - Mercedes Garayoa
- Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Complejo Asistencial Universitario de Salamanca-IBSAL, Department of Hematology, 37007 Salamanca, Spain; (A.D.-T.); (M.L.-M.); (N.P.); (R.G.-S.); (M.-V.M.); (M.G.)
| | - Teresa Paíno
- Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Complejo Asistencial Universitario de Salamanca-IBSAL, Department of Hematology, 37007 Salamanca, Spain; (A.D.-T.); (M.L.-M.); (N.P.); (R.G.-S.); (M.-V.M.); (M.G.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, CB16/12/00233), Instituto de Salud Carlos III, 37007 Salamanca, Spain
- Correspondence: ; Tel.: +34-923-294-812; Fax: +34-923-294-743
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Oncolytic Virotherapy and Microenvironment in Multiple Myeloma. Int J Mol Sci 2021; 22:ijms22052259. [PMID: 33668361 PMCID: PMC7956262 DOI: 10.3390/ijms22052259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/17/2021] [Accepted: 02/20/2021] [Indexed: 12/28/2022] Open
Abstract
Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of bone marrow (BM) clonal plasma cells, which are strictly dependent on the microenvironment. Despite the improvement of MM survival with the use of new drugs, MM patients still relapse and become always refractory to the treatment. The development of new therapeutic strategies targeting both tumor and microenvironment cells are necessary. Oncolytic virotherapy represent a promising approach in cancer treatment due to tumor-specific oncolysis and activation of the immune system. Different types of human viruses were checked in preclinical MM models, and the use of several viruses are currently investigated in clinical trials in MM patients. More recently, the use of alternative non-human viruses has been also highlighted in preclinical studies. This strategy could avoid the antiviral immune response of the patients against human viruses due to vaccination or natural infections, which could invalid the efficiency of virotherapy approach. In this review, we explored the effects of the main oncolytic viruses, which act through both direct and indirect mechanisms targeting myeloma and microenvironment cells inducing an anti-MM response. The efficacy of the oncolytic virus-therapy in combination with other anti-MM drugs targeting the microenvironment has been also discussed.
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The Immune Microenvironment in Multiple Myeloma: Friend or Foe? Cancers (Basel) 2021; 13:cancers13040625. [PMID: 33562441 PMCID: PMC7914424 DOI: 10.3390/cancers13040625] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/27/2021] [Accepted: 02/02/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary The crosstalk between multiple myeloma and immune cells within the bone marrow niche has been identified as an emerging hallmark of this hematological disease. As our knowledge on this interplay increases, it becomes more evident that successful treatment approaches need to boost the body’s natural defenses through immunotherapy. The present review will focus on the mechanisms by which myeloma cancer cells turn immune populations into their “partners in crime”. Additionally, we will provide an overview of currently ongoing pre-clinical studies targeting the bone marrow immune microenvironment. Abstract Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and suppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations.
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Calmeiro J, Mendes L, Duarte IF, Leitão C, Tavares AR, Ferreira DA, Gomes C, Serra J, Falcão A, Cruz MT, Carrascal MA, Neves BM. In-Depth Analysis of the Impact of Different Serum-Free Media on the Production of Clinical Grade Dendritic Cells for Cancer Immunotherapy. Front Immunol 2021; 11:593363. [PMID: 33613517 PMCID: PMC7893095 DOI: 10.3389/fimmu.2020.593363] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/17/2020] [Indexed: 12/15/2022] Open
Abstract
Dendritic cell (DC)-based antitumor vaccines have proven to be a safe approach, but often fail to generate robust results between trials. Translation to the clinic has been hindered in part by the lack of standard operation procedures for vaccines production, namely the definition of optimal culture conditions during ex-vivo DC differentiation. Here we sought to compare the ability of three clinical grade serum-free media, DendriMACS, AIM-V, and X-VIVO 15, alongside with fetal bovine serum-supplemented Roswell Park Memorial Institute Medium (RPMI), to support the differentiation of monocyte-derived DCs (Mo-DCs). Under these different culture conditions, phenotype, cell metabolomic profiles, response to maturation stimuli, cytokines production, allogenic T cell stimulatory capacity, as well as priming of antigen-specific CD8+ T cells and activation of autologous natural killer (NK) cells were analyzed. Immature Mo-DCs differentiated in AIM-V or X-VIVO 15 presented lower levels of CD1c, CD1a, and higher expression of CD11c, when compared to cells obtained with DendriMACS. Upon stimulation, only AIM-V or X-VIVO 15 DCs acquired a full mature phenotype, which supports their enhanced capacity to polarize T helper cell type 1 subset, to prime antigen-specific CD8+ T cells and to activate NK cells. CD8+ T cells and NK cells resulting from co-culture with AIM-V or X-VIVO 15 DCs also showed superior cytolytic activity. 1H nuclear magnetic resonance-based metabolomic analysis revealed that superior DC immunostimulatory capacities correlate with an enhanced catabolism of amino acids and glucose. Overall, our data highlight the impact of critically defining the culture medium used in the production of DCs for clinical application in cancer immunotherapy. Moreover, the manipulation of metabolic state during differentiation could be envisaged as a strategy to enhance desired cell characteristics.
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Affiliation(s)
- João Calmeiro
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Luís Mendes
- CICECO, Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Iola F Duarte
- CICECO, Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Catarina Leitão
- Department of Medical Sciences and Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
| | - Adriana R Tavares
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Daniel Alexandre Ferreira
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Célia Gomes
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal
| | | | - Amílcar Falcão
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), University of Coimbra, Coimbra, Portugal
| | - Maria Teresa Cruz
- Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.,Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | | | - Bruno Miguel Neves
- Department of Medical Sciences and Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
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Role of Aiolos and Ikaros in the Antitumor and Immunomodulatory Activity of IMiDs in Multiple Myeloma: Better to Lose Than to Find Them. Int J Mol Sci 2021; 22:ijms22031103. [PMID: 33499314 PMCID: PMC7865245 DOI: 10.3390/ijms22031103] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/17/2021] [Accepted: 01/19/2021] [Indexed: 12/31/2022] Open
Abstract
The Ikaros zing-finger family transcription factors (IKZF TFs) are important regulators of lymphocyte development and differentiation and are also highly expressed in B cell malignancies, including Multiple Myeloma (MM), where they are required for cancer cell growth and survival. Moreover, IKZF TFs negatively control the functional properties of many immune cells. Thus, the targeting of these proteins has relevant therapeutic implications in cancer. Indeed, accumulating evidence demonstrated that downregulation of Ikaros and Aiolos, two members of the IKZF family, in malignant plasma cells as well as in adaptative and innate lymphocytes, is key for the anti-myeloma activity of Immunomodulatory drugs (IMiDs). This review is focused on IKZF TF-related pathways in MM. In particular, we will address how the depletion of IKZF TFs exerts cytotoxic effects on MM cells, by reducing their survival and proliferation, and concomitantly potentiates the antitumor immune response, thus contributing to therapeutic efficacy of IMiDs, a cornerstone in the treatment of this neoplasia.
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Abstract
Multiple myeloma remains an incurable disease despite great advances in its therapeutic landscape. Increasing evidence supports the belief that immune dysfunction plays an important role in the disease pathogenesis, progression, and drug resistance. Recent efforts have focused on harnessing the immune system to exert anti-myeloma effects with encouraging outcomes. First-in-class anti-CD38 monoclonal antibody, daratumumab, now forms part of standard treatment regimens in relapsed and refractory settings and is shifting to front-line treatments. However, a non-negligible number of patients will progress and be triple refractory from the first line of treatment. Antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptors (CAR) are being developed in a heavily pretreated setting with outstanding results. Belantamab mafodotin-blmf has already received approval and other anti-B-cell maturation antigen (BCMA) therapies (CARs and bispecific antibodies are expected to be integrated in therapeutic options against myeloma soon. Nonetheless, immunotherapy faces different challenges in terms of efficacy and safety, and manufacturing and economic drawbacks associated with such a line of therapy pose additional obstacles to broadening its use. In this review, we described the most important clinical data on immunotherapeutic agents, delineated the limitations that lie in immunotherapy, and provided potential insights to overcome such issues.
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Ye X, Li W, Huang J, Zhang L, Zhang Y. Cytotoxic T Cell Responses Induced by CS1/CRT Fusion DNA Vaccine in a Human Plasmacytoma Model. Front Oncol 2020; 10:587237. [PMID: 33330069 PMCID: PMC7714938 DOI: 10.3389/fonc.2020.587237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 10/23/2020] [Indexed: 11/18/2022] Open
Abstract
To date, multiple myeloma remains an incurable disease. Immunotherapy is an encouraging option in the development of multiple myeloma (MM) therapy. CS1 is a specific myeloma antigen, which is highly expressed in myeloma cells. Calreticulin (CRT) is a key determinant of cell death, which can influence antigen presentation and promote cellular phagocytic uptake. In the current study, we constructed a DNA vaccine encoding both CS1 and CRT. Our results show that the PcDNA3.1-CS1/CRT vaccine was able to induce cytotoxic T cell responses against myeloma cells in vivo, and the tumor growth was significantly suppressed in mice immunized with this vaccine. Therefore, our findings indicate that the CS1/CRT fusion DNA vaccine may represent a promising novel myeloma therapy, and the potential for combining the CS1/CRT vaccine with other myeloma treatments.
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Affiliation(s)
- Xueshi Ye
- Department of Hematology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wanli Li
- Department of Orthopedics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jinwen Huang
- Department of Hematology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lifei Zhang
- Department of Hematology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ye Zhang
- Department of Hematology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Saunders R, Kaur D, Desai D, Berair R, Chachi L, Thompson RD, Siddiqui SH, Brightling CE. Fibrocyte localisation to the ASM bundle in asthma: bidirectional effects on cell phenotype and behaviour. Clin Transl Immunology 2020; 9:e1205. [PMID: 33209301 PMCID: PMC7662089 DOI: 10.1002/cti2.1205] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 09/21/2020] [Accepted: 10/09/2020] [Indexed: 12/11/2022] Open
Abstract
Objectives Airway hyper‐responsiveness and persistent airflow obstruction contribute to asthma pathogenesis and symptoms, due in part to airway smooth muscle (ASM) hypercontractility and increased ASM mass. Fibrocytes have been shown to localise to the ASM in asthma however it is not known whether fibrocytes localise to the ASM in nonasthmatic eosinophilic bronchitis (NAEB) and chronic obstructive pulmonary disease (COPD). In addition, the potential consequences of fibrocyte localisation to ASM as regards asthma pathophysiology has not been widely studied. Methods Fibrocytes and proliferating cells were enumerated in ASM in bronchial tissue using immunohistochemistry. The effects of primary ASM and fibrocytes upon each other in terms of phenotype and behaviour following co‐culture were investigated by assessing cell number, size, apoptotic status, phenotype and contractility in in vitro cell‐based assays. Results Increased fibrocyte number in the ASM was observed in asthma versus NAEB, but not NAEB and COPD versus controls, and confirmed in asthma versus controls. ASM proliferation was not detectably different in asthmatics versus healthy controls in vivo. No difference in proliferation, apoptotic status or size of ASM was seen following culture with/without fibrocytes. Following co‐culture with ASM from asthmatics versus nonasthmatics, fibrocyte smooth muscle marker expression and collagen gel contraction were greater. Following co‐culture, fibrocyte CD14 expression was restored with the potential to contribute to asthma pathogenesis via monocyte‐mediated processes dependent on the inflammatory milieu. Conclusion Further understanding of mechanisms of fibrocyte recruitment to and/or differentiation within the ASM may identify novel therapeutic targets to modulate ASM dysfunction in asthma.
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Affiliation(s)
- Ruth Saunders
- Department of Respiratory Sciences Institute for Lung Health University of Leicester Leicester UK
| | - Davinder Kaur
- Department of Respiratory Sciences Institute for Lung Health University of Leicester Leicester UK
| | - Dhananjay Desai
- Department of Respiratory Sciences Institute for Lung Health University of Leicester Leicester UK.,Present address: University Hospitals Coventry & Warwickshire NHS Trust Coventry UK
| | - Rachid Berair
- Department of Respiratory Sciences Institute for Lung Health University of Leicester Leicester UK.,Present address: The Royal Wolverhampton NHS Trust Wolverhampton UK
| | - Latifa Chachi
- Department of Respiratory Sciences Institute for Lung Health University of Leicester Leicester UK
| | | | - Salman H Siddiqui
- Department of Respiratory Sciences Institute for Lung Health University of Leicester Leicester UK
| | - Christopher E Brightling
- Department of Respiratory Sciences Institute for Lung Health University of Leicester Leicester UK
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Zanwar S, Nandakumar B, Kumar S. Immune-based therapies in the management of multiple myeloma. Blood Cancer J 2020; 10:84. [PMID: 32829378 PMCID: PMC7443188 DOI: 10.1038/s41408-020-00350-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/24/2020] [Accepted: 07/27/2020] [Indexed: 12/14/2022] Open
Abstract
Multiple myeloma (MM) is a clonal plasma cell malignancy affecting a predominantly elderly population. The continued development of newer therapies with novel mechanisms of action has reshaped the treatment paradigm of this disorder in the last two decades, leading to a significantly improved prognosis. This has in turn resulted in an increasing number of patients in need of therapy for relapsed/refractory disease. Immune-based therapies, including monoclonal antibodies, immune checkpoint inhibitors, and most promisingly, adoptive cellular therapies represent important therapeutic strategies in these patients due to their non-cross resistant mechanisms of actions with the usual frontline therapies comprising of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). The anti-CD38 antibodies daratumumab and more recently isatuximab, with their excellent efficacy and safety profile along with its synergy in combination with IMiDs and PIs, are being increasingly incorporated in the frontline setting. Chimeric antigen receptor-T cell (CART) therapies and bi-specific T-cell engager (BiTE) represent exciting new options that have demonstrated efficacy in heavily pretreated and refractory MM. In this review, we discuss the rationale for use of immune-based therapies in MM and summarize the currently available literature for common antibodies and CAR-T therapies that are utilized in MM.
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Affiliation(s)
- Saurabh Zanwar
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Shaji Kumar
- Division of Hematology, Mayo Clinic, Rochester, MN, USA.
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
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Beyond DNA Damage: Exploring the Immunomodulatory Effects of Cyclophosphamide in Multiple Myeloma. Hemasphere 2020; 4:e350. [PMID: 32309787 PMCID: PMC7162079 DOI: 10.1097/hs9.0000000000000350] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/30/2020] [Accepted: 02/07/2020] [Indexed: 12/22/2022] Open
Abstract
The alkylating agent cyclophosphamide has been used in the treatment of multiple myeloma for over 60 years. At low doses, cyclophosphamide also has significant immunomodulatory activity, which can be used to modify the immunosuppressive tumor microenvironment in order to augment responses to existing therapies. Immune-mediated therapies are becoming more widespread in modern approaches to myeloma treatment. In this review, we discuss the effects cyclophosphamide has on the immune system, and how it can be used synergistically with other treatment modalities including the immunomodulatory agents, monoclonal antibodies and cellular therapies.
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