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Human Mesothelioma Induces Defects In Dendritic Cell Numbers And Antigen-processing Function Which Predict Survival Outcomes
S. Cornwall, M. Wikstrom, A. Musk, J. Alvarez, A. Nowak, D. Nelson
Published 2016 · Medicine
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ABSTRACT Mesothelioma is an almost invariably fatal tumor with chemotherapy extending survival by a few months. One immunotherapeutic strategy is to target dendritic cells (DCs), key antigen-presenting cells involved in antigen presentation, to induce antigen-specific T cell responses. However, DC-targeting will only be effective if DCs are fit-for-purpose, and the functional status of DCs in mesothelioma patients was not clear. We found that mesothelioma patients have significantly decreased numbers of circulating myeloid (m)DC1 cells, mDC2 cells and plasmacytoid (p)DCs relative to healthy age and gender-matched controls. Blood monocytes from patients could not differentiate into immature monocyte-derived DCs (MoDCs), indicated by a significantly reduced ability to process antigen and reduced expression of costimulatory (CD40, CD80 and CD86) and MHC (HLA-DR) molecules, relative to controls. Activation of mesothelioma-derived MoDCs with LPS+/-IFNγ generated partially mature MoDCs, evident by limited upregulation of the maturation marker, CD83, and the costimulatory markers. Attempts to rescue mesothelioma-derived DC function using CD40Ligand(L) also failed, indicated by maintenance of antigen-processing capacity and limited upregulation of CD40, CD83, CD86 and HLA-DR. These data suggest that mesothelioma patients have significant numerical and functional DC defects and that their reduced capacity to process antigen and reduced expression of costimulatory molecules could induce anergized/tolerized T cells. Nonetheless, survival analyses revealed that individuals with mesothelioma and higher than median levels of mDC1s and/or whose MoDCs matured in response to LPS, IFNγ or CD40L lived longer, implying their selection for DC-targeting therapy could be promising especially if combined with another treatment modality.
This paper references
CD154 inhibits tumor‐induced apoptosis in dendritic cells and tumor growth
C. Esche (1999)
The efficacy of tumor debulking surgery is improved by adjuvant immunotherapy using imiquimod and anti-CD40
Andrea Khong (2014)
Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling
S. Robbins (2007)
IL-2/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector/memory phase.
C. Jackaman (2012)
Characterization of circulating blood dendritic cell subsets DC123+ (Lymphoid) and DC11C+ (myeloid) in prostate adenocarcinoma patients
S. Alessandro (2007)
Maturation of circulating dendritic cells and imbalance of T-cell subsets in patients with squamous cell carcinoma of the head and neck
K. Sakakura (2005)
Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases
A. D. Giacomo (2008)
IL-2 Intratumoral Immunotherapy Enhances CD8+ T Cells That Mediate Destruction of Tumor Cells and Tumor-Associated Vasculature: A Novel Mechanism for IL-2 1
C. Jackaman (2003)
Antigen-Processing Machinery in Human Dendritic Cells: Up-Regulation by Maturation and Down-Regulation by Tumor Cells1
T. Whiteside (2004)
Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study.
L. Calabrò (2015)
Proliferating dendritic cell progenitors in human blood
N. Romani (1994)
Alterations in the frequency of dendritic cell subsets in the peripheral circulation of patients with squamous cell carcinomas of the head and neck.
T. Hoffmann (2002)
Deliberately provoking local inflammation drives tumors to become their own protective vaccine site.
C. Jackaman (2008)
High Blood Neutrophil-to-Lymphocyte Ratio Is an Indicator of Poor Prognosis in Malignant Mesothelioma Patients Undergoing Systemic Therapy
S. Kao (2010)
CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients
P. Ott (2013)
Factors associated with survival in a large series of patients with malignant pleural mesothelioma in New South Wales
A. Linton (2014)
Dendritic cells: unique leukocyte populations which control the primary immune response.
D. Hart (1997)
Anti-PD-1 therapy in melanoma.
B. Homet Moreno (2015)
CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha
C. Caux (1996)
Inhibition of dendritic cell migration by transforming growth factor-β1 increases tumor-draining lymph node metastasis
K. Imai (2012)
Reciprocal control of T helper cell and dendritic cell differentiation.
M. Rissoan (1999)
Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028 American Association for Cancer
E W Alley
In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb
O. Murillo (2009)
Synergistic Effect of CTLA-4 Blockade and Cancer Chemotherapy in the Induction of Anti-Tumor Immunity
W. Lesterhuis (2013)
Age-related oxidative stress compromises endosomal proteostasis.
Elvira S. Cannizzo (2012)
Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling. Genome biology 2008; 9:R17
SH Robbins (2008)
Dysfunctional and short-lived subsets in monocyte-derived dendritic cells from patients with advanced cancer.
H. Onishi (2002)
Enumeration of blood dendritic cells in patients with multiple myeloma at presentation and through therapy
S. Harrison (2008)
From plasmacytoid to dendritic cell: Morphological and functional switches during plasmacytoid pre‐dendritic cell differentiation
V. Soumelis (2006)
Regulatory T cells and cytokines in malignant pleural effusions secondary to mesothelioma and carcinoma
P. Delong (2005)
Latency periods in asbestos-related mesothelioma of the pleura.
C. Bianchi (1997)
Locally Administered TLR7 Agonists Drive Systemic Antitumor Immune Responses That Are Enhanced by Anti-CD40 Immunotherapy1
Steve A. Broomfield (2009)
Cutting Edge: Tumor-Specific CTL Are Constitutively Cross-Armed in Draining Lymph Nodes and Transiently Disseminate to Mediate Tumor Regression following Systemic CD40 Activation1
P. Stumbles (2004)
The New England Journal of Medicine
Tumor‐infiltrating dendritic cells exhibit defective cross‐presentation of tumor antigens, but is reversed by chemotherapy
A. McDonnell (2015)
Mouse and human dendritic cell subtypes
K. Shortman (2002)
CD1a expression defines an interleukin‐12 producing population of human dendritic cells
M. Cernadas (2009)
Immunity and malignant mesothelioma: from mesothelial cell damage to tumor development and immune response-based therapies.
V. Izzi (2012)
Local effector failure in mesothelioma is not mediated by CD4+ CD25+ T-regulator cells
C. Jackaman (2009)
Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors.
A. Nowak (2003)
Partial restoration of T‐cell function in aged mice by in vitro blockade of the PD‐1/ PD‐L1 pathway
C. S. Lages (2010)
Pancreatic adenocarcinoma exerts systemic effects on the peripheral blood myeloid and plasmacytoid dendritic cells: an indicator of disease severity?
Vegard Tjomsland (2009)
Sunitinib-Induced Myeloid Lineage Redistribution in Renal Cell Cancer Patients: CD1c+ Dendritic Cell Frequency Predicts Progression-Free Survival
H. van Cruijsen (2008)
GMCSF Mouse Bone Marrow Cultures Comprise a Heterogeneous Population of CD11c(+)MHCII(+) Macrophages and Dendritic Cells
J Helft (2015)
Generation of interferon alpha-producing predendritic cell (Pre-DC)2 from human CD34(+) hematopoietic stem cells
B Blom (2000)
Partial, but not complete, tumor-debulking surgery promotes protective antitumor memory when combined with chemotherapy and adjuvant immunotherapy.
Steve A. Broomfield (2005)
In Vivo Cross-Presentation of a Soluble Protein Antigen: Kinetics, Distribution, and Generation of Effector CTL Recognizing Dominant and Subdominant Epitopes1
D. Nelson (2000)
Immunobiology of dendritic cells.
J. Banchereau (2000)
Phenotypic characterisation of the dendritic cell infiltrate in prostate cancer.
A. Troy (1998)
Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.
L. Calabrò (2013)
GM-CSF Mouse Bone Marrow Cultures Comprise a Heterogeneous Population of CD11c(+)MHCII(+) Macrophages and Dendritic Cells.
Julie Helft (2015)
Anti-PD-1 Therapy in Melanoma. Seminars in oncology
B Homet Moreno (2015)
Numerical and functional defects of blood dendritic cells in early- and late-stage breast cancer
A. Pinzón-Charry (2007)
Decreased antigen presentation by dendritic cells in patients with breast cancer.
D. Gabrilovich (1997)
Major Cancer Regressions in Mesothelioma After Treatment with an Anti-Mesothelin Immunotoxin and Immune Suppression
R. Hassan (2013)
The Enigmatic Plasmacytoid T Cells Develop into Dendritic Cells with Interleukin (IL)-3 and CD40-Ligand
Géraldine Grouard (1997)
Therapeutic influence on circulating and monocyte-derived dendritic cells in laryngeal squamous cell carcinoma patients
X. Ma (2009)
Immunology of aging and cancer development.
T. Fulop (2013)
A Phase I Clinical Trial of Single-Dose Intrapleural IFN-β Gene Transfer for Malignant Pleural Mesothelioma and Metastatic Pleural Effusions: High Rate of Antitumor Immune Responses
D. Sterman (2007)
Tumor-derived factors impaired motility and immune functions of dendritic cells through derangement of biophysical characteristics and reorganization of cytoskeleton.
Z. Zeng (2007)
Mouse Bone Marrow Cultures Comprise a Heterogeneous Population of CD11c(+)MHCII(+) Macrophages and Dendritic Cells
J Helft (2015)
Is cancer vaccination feasible at older age?
C. Gravekamp (2014)
The Use of Agonistic Anti-CD40 Therapy in Treatments for Cancer
Andrea Khong (2012)
Vascular Endothelial Growth Factor-Trap Overcomes Defects in Dendritic Cell Differentiation but Does Not Improve Antigen-Specific Immune Responses
Ingo Fricke (2007)
Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. The Lancet Respiratory medicine
L Calabro (2015)
Abstract CT103: Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028
E. Alley (2015)
Quantitative and functional defects of dendritic cells in classic Kaposi's sarcoma.
S. Della Bella (2006)
Characterization of circulating blood dendritic cell subsets DC123+ (lymphoid) and DC11C+ (myeloid) in prostate adenocarcinoma patients.
A. Sciarra (2007)
Dendritic cells with immature phenotype and defective function in the peripheral blood from patients with hepatocellular carcinoma.
T. Ninomiya (1999)
Generation of Interferon α–Producing Predendritic Cell (Pre-Dc)2 from Human Cd34+ Hematopoietic Stem Cells
B. Blom (2000)
CD40‐activated B cells contribute to mesothelioma tumor regression
C. Jackaman (2011)
Advances in malignant mesothelioma.
B. Robinson (2005)
This paper is referenced by
A single centre phase II trial to assess the immunological activity of TroVax® plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma – the SKOPOS trial
J. Lester (2018)
Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge
D. M. Abbott (2020)
Tumor microenvironment-related dendritic cell deficiency: a target to enhance tumor immunotherapy.
S. Zhu (2020)
Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients
Swati Khanna (2018)
T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma
H. Vroman (2020)
Innate Immune Cells: A Potential and Promising Cell Population for Treating Osteosarcoma
Z. Wang (2019)
Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy
Floris Dammeijer (2017)
Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS
P. D. de Goeje (2018)
Trial watch: Dendritic cell-based anticancer immunotherapy
Abhishek D Garg (2017)
The role of dendritic cells in cancer.
Yoke Seng Lee (2019)
Acidosis-Induced TGF-β2 Production Promotes Lipid Droplet Formation in Dendritic Cells and Alters Their Potential to Support Anti-Mesothelioma T Cell Response
Natalia Trempolec (2020)
Photodynamic Therapy-Based Dendritic Cell Vaccination Suited to Treat Peritoneal Mesothelioma
Natalia Trempolec (2020)
Heterogeneous Contributing Factors in MPM Disease Development and Progression: Biological Advances and Clinical Implications
B. Tolani (2018)
Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics
Abhishek D Garg (2017)
Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human
J. Aerts (2017)
Cellular Immunotherapy and Locoregional Administration of CAR T-Cells in Malignant Pleural Mesothelioma
Robert A. Belderbos (2020)