← Back to Search
The Immune Microenvironment In Mesothelioma: Mechanisms Of Resistance To Immunotherapy
G. Chu, Nico van Zandwijk, J. E. J. Rasko
Published 2019 · Medicine
Download PDFAnalyze on Scholarcy
Although mesothelioma is the consequence of a protracted immune response to asbestos fibers and characterized by a clear immune infiltrate, novel immunotherapy approaches show less convincing results as compared to those seen in melanoma and non-small cell lung cancer. The immune suppressive microenvironment in mesothelioma is likely contributing to this therapy resistance. Therefore, it is important to explore the characteristics of the tumor microenvironment for explanations for this recalcitrant behavior. This review describes the stromal, cytokine, metabolic, and cellular milieu of mesothelioma, and attempts to make connection with the outcome of immunotherapy trials.
This paper references
Targeting Tie-2/angiopoietin axis in experimental mesothelioma confers differential responses and raises predictive implications
Sophia F Magkouta (2018)
past results and recent developments
S Tomek (2003)
HIF1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment
CA Corzo (2010)
a phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: safety and efficacy
PS Adusumilli (2019)
Expression and prognostic significance of hypoxia - inducible factor 1 alpha ( HIF - 1 alpha ) in malignant pleural mesothelioma ( MPM )
A Klabatsa (2006)
recent progress and potential biomarkers
P Darvin (2018)
Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial.
A. Scherpereel (2019)
F. Ribeiro (2017)
Circulating and tumor‐infiltrating myeloid cells predict survival in human pleural mesothelioma
B. Burt (2011)
Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer
S. Nagaraj (2007)
Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling.
G. Gordon (2005)
Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma
K. Donaldson (2009)
Natural Killer Cells from Malignant Pleural Effusion Are Endowed with a Decidual-Like Proangiogenic Polarization
Annalisa Bosi (2018)
PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma
R. Kanteti (2016)
Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma.
Masaki Anraku (2008)
NK‐ and T‐cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti‐CTLA‐4 therapy
Rosa Sottile (2019)
Complex Immune Contextures Characterise Malignant Peritoneal Mesothelioma: Loss of Adaptive Immunological Signature in the More Aggressive Histological Types
M. Tazzari (2018)
TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth
M. Fujii (2012)
Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma
E. Marcq (2017)
The expression of CXCR4, CXCL12 and CXCR7 in malignant pleural mesothelioma
T. Li (2011)
Abstract CT 036 : a phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin - targeted CAR T cells : safety and efficacy
Global Gene Expression Profiling Of Human Pleural Mesotheliomas: Identification of Matrix Metalloproteinase 14 (MMP-14) as Potential Tumour Target
S. Crispi (2009)
Differential effects of malignant mesothelioma cells on THP-1 monocytes and macrophages.
V. Izzi (2009)
Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma
N. Miselis (2008)
Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards
V. Bronte (2016)
Angiogenesis is an independent prognostic factor in malignant mesothelioma
J. Edwards (2001)
Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients.
J. Schmielau (2001)
Results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial
S Popat (2019)
Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells
A. Facciabene (2011)
Expression of a Functional CCR2 Receptor Enhances Tumor Localization and Tumor Eradication by Retargeted Human T cells Expressing a Mesothelin-Specific Chimeric Antibody Receptor
Edmund K. Moon (2011)
The PDL1-PD1 Axis Converts Human TH1 Cells into Regulatory T Cells
S. Amarnath (2011)
Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network.
Q. Li (2011)
Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation
M. Cioce (2014)
IL-2/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector/memory phase.
C. Jackaman (2012)
Introducing the new BTS guideline: the investigation and management of pleural malignant mesothelioma
I. Woolhouse (2018)
Regulatory T cells and cytokines in malignant pleural effusions secondary to mesothelioma and carcinoma
P. Delong (2005)
Chrysotile fiber is a strong mutagen in mammalian cells.
T. Hei (1992)
Characterization of hypoxia in malignant pleural mesothelioma with FMISO PET-CT.
R. Francis (2015)
Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma. Oncoimmunology
E Marcq (2017)
Turning foes to friends: targeting cancer-associated fibroblasts
Xueman Chen (2018)
Asbestos exposure induces MCP-1 secretion by pleural mesothelial cells.
S. Tanaka (2000)
P2.06-026 A Phase II Trial of the Oral FGF Receptor Inhibitor AZD4547 as 2nd or 3rd Line Therapy in Malignant Pleural Mesothelioma - Trial in Progress: Topic: Mesothelioma and SCLC
Wei-Sen Lam (2017)
Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
E. Alley (2017)
Comparative immunohistochemical analysis of IMP3, GLUT1, EMA, CD146, and desmin for distinguishing malignant mesothelioma from reactive mesothelial cells.
H. Minato (2014)
Pirfenidone decreases mesothelioma cell proliferation and migration via inhibition of ERK and AKT and regulates mesothelioma tumor microenvironment in vivo
C. Li (2018)
Intra-tumoural regulatory T cells: a potential new target in cancer immunotherapy.
D. J. Needham (2006)
Ratio of Intratumoral Macrophage Phenotypes Is a Prognostic Factor in Epithelioid Malignant Pleural Mesothelioma
R. Cornelissen (2014)
Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression.
A. Doedens (2010)
TGF-b synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth
M. Fujii (2012)
Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab
A. Mitsuhashi (2015)
Participation of nitric oxide and iron in the oxidation of DNA in asbestos-treated human lung epithelial cells.
C. Chao (1996)
PDL1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation
MZ Noman (2014)
Abundant expression of TIM-3, LAG-3, PD-1 and PD-L1 as immunotherapy checkpoint targets in effusions of mesothelioma patients
E. Marcq (2017)
Analysis of Expression of Programmed Cell Death 1 Ligand 1 (PD-L1) in Malignant Pleural Mesothelioma (MPM)
S. Cedrés (2015)
Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations
R. Bueno (2016)
Longitudinal Measurement of Pleural Fluid Biochemistry and Cytokines in Malignant Pleural Effusions.
Rajesh Thomas (2016)
Hepatocyte growth factor/scatter factor stimulates chemotaxis and growth of malignant mesothelioma cells through c‐met receptor
J. Klominek (1998)
Increased Levels of C-C Chemokine RANTES in Asbestos Exposed Workers and in Malignant Mesothelioma Patients from an Hyperendemic Area
M. Comar (2014)
Angiogenic cytokines in mesothelioma: a study of VEGF, FGF‐1 and ‐2, and TGF β expression
S. Kumar-Singh (1999)
The parallel lives of angiogenesis and immunosuppression: cancer and other tales
Gregory T. Motz (2011)
a randomised, controlled, open-label, phase 3 trial
G Zalcman (2016)
Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma
I. C. Salaroglio (2015)
TNF-alpha receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers.
J. Y. Liu (1998)
Expression and prognostic significance of hypoxia-inducible factor 1alpha (HIF-1alpha) in malignant pleural mesothelioma (MPM). Lung Cancer
A Klabatsa (2006)
TNF-α inhibits asbestos-induced cytotoxicity via a NF-κB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis
H. Yang (2006)
Transforming growth factor-beta 1 (TGF-beta 1)- and beta 2-like activities in malignant pleural effusions caused by malignant mesothelioma or primary lung cancer.
J. Maeda (1994)
Immune checkpoint inhibitors: recent progress and potential biomarkers
Pramod Darvin (2018)
Natural killer cells from malignant pleural effusion are endowed with a deciduallike proangiogenic polarization
A Bosi (2018)
Mesothelioma and tumor-associated autoantibodies. D31 Nonpulmonary critical care and monitoring
C J Chapman (2011)
Prognostic value of the lymphocyte-to-monocyte ratio and other inflammatory markers in malignant pleural mesothelioma
A. C. Tanrıkulu (2016)
Chemotherapy for malignant pleural mesothelioma: past results and recent developments
S. Tomek (2003)
CCL2, Galectin-3, and SMRP Combination Improves the Diagnosis of Mesothelioma in Pleural Effusions
C. Blanquart (2012)
VISTA expressed in tumour cells regulates T cell function
Kumuluzi Mulati (2018)
Differential motile response of human malignant mesothelioma cells to fibronectin, laminin and collagen type IV: The role of β1 integrins
J. Klominek (1997)
Pleural Effusions from Patients with Mesothelioma Induce Recruitment of Monocytes and Their Differentiation into M2 Macrophages
Anne-Laure Chéné (2016)
Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group.
A. Husain (2018)
Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity
P. Adusumilli (2014)
Phase II trial of pembrolizumab (P) in patients (pts) with previouslytreated mesothelioma (MM)
A Desai (2018)
Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells.
O. Kawalekar (2016)
c-Met expression and MET amplification in malignant pleural mesothelioma.
Melanie C. Bois (2016)
Matrix metalloproteinases 2 and 9 (gelatinases A and B) expression in malignant mesothelioma and benign pleura
J. Edwards (2003)
Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses
J. Hegmans (2006)
a double-blind, randomised, placebo-controlled phase 3 trial
GV Scagliotti (2019)
Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy.
K. Schelch (2014)
Sera from patients with malignant mesothelioma can contain autoantibodies.
C. Robinson (1998)
Hypoxia and metabolism: Hypoxia, DNA repair and genetic instability
R. Bristow (2008)
Demographics, management and survival of patients with malignant pleural mesothelioma in the National Lung Cancer Audit in England and Wales.
P. Beckett (2015)
Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages.
Trudy J. Padmore (2017)
How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing and somatic mutations
H. Rehrauer (2017)
preliminary results from a nonrandomised, open-label, phase 1b trial
EW Alley (2017)
Origin of cancer-associated fibroblasts and tumor-associated macrophages in humans after sex-mismatched bone marrow transplantation
Masako Kurashige (2018)
Tryptase Mast Cells in Malignant Pleural Mesothelioma as an Independent Favorable Prognostic Factor
G. Alí (2009)
Chemotaxis and haptotaxis of human malignant mesothelioma cells: effects of fibronectin, laminin, type IV collagen, and an autocrine motility factor-like substance.
J. Klominek (1993)
Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency
J. Feucht (2018)
cancer and other tales
GT Motz (2011)
Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
M. Maio (2017)
Phase II trial of pembrolizumab (P) in patients (pts) with previously-treated mesothelioma (MM).
A. Desai (2018)
Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107).
T. Jahan (2012)
Targeting the C-terminus of galectin-9 induces mesothelioma apoptosis and M2 macrophage depletion
P. Bertino (2019)
HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment
C. Corzo (2010)
Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation
H. Yang (2010)
Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients
Swati Khanna (2018)
The role of myeloid cells in the promotion of tumour angiogenesis
C. Murdoch (2008)
targeting cancerassociated fibroblasts
X Chen (2019)
Four immunohistochemical assays to measure the PD-L1 expression in malignant pleural mesothelioma
T. Watanabe (2018)
Multimodality treatment of malignant pleural mesothelioma with or without immunotherapy: does it change anything?
M. Lucchi (2010)
Identification of novel markers for the diagnosis of malignant pleural mesothelioma.
F. Gueugnon (2011)
Audit in England and Wales
AN Husain (2015)
The PDL1PD1 axis converts human TH1 cells into regulatory T cells
S Amarnath (2011)
The “don't eat me” signal CD47 is a novel diagnostic biomarker and potential therapeutic target for diffuse malignant mesothelioma
C. Schürch (2017)
Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma
K. Kiyotani (2017)
British Thoracic Society Guideline for the investigation and management of malignant pleural mesothelioma
I. Woolhouse (2018)
Cytotoxic T Cells in PD-L1–Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors
M. Awad (2016)
Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma
N. S. Patil (2018)
Asbestos causes DNA strand breaks in cultured pulmonary epithelial cells: role of iron-catalyzed free radicals.
D. Kamp (1995)
Clinical impact and reliability of pleural fluid mesothelin in undiagnosed pleural effusions.
H. E. Davies (2009)
PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation
M. Noman (2014)
Pembrolizumab as Palliative Immunotherapy in Malignant Pleural Mesothelioma
Y. Metaxas (2018)
NK cells from malignant pleural effusions are not anergic but produce cytokines and display strong antitumor activity on short‐term IL‐2 activation
P. Vacca (2013)
Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications
Y. Blum (2019)
Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605)
R. Pietrofesa (2016)
Evaluating the effect of immune cells on the outcome of patients with mesothelioma
S. Chee (2017)
A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma
E. V. van Brummelen (2019)
Metabolic Barriers to T Cell Function in Tumors
A. Sugiura (2018)
Participation of iron and nitric oxide in the mutagenicity of asbestos in hgprt-, gpt+ Chinese hamster V79 cells.
S. H. Park (1998)
a multicentre, openlabel, randomised, non-comparative, phase 2 trial
A Scherpereel (2019)
Cyclooxygenase-2 expression is a novel prognostic factor in malignant mesothelioma.
J. Edwards (2002)
Transforming growth factor‐beta 1 (TGF‐β1)‐ and β2‐like activities in malignant pleural effusions caused by malignant mesothelioma or primary lung cancer
J. Maeda (1994)
Chemokine receptors are infrequently expressed in malignant and benign mesothelial cells.
B. Davidson (2007)
Neoantigenic Potential of Complex Chromosomal Rearrangements in Mesothelioma
A. Mansfield (2019)
How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations
H. Rehrauer (2018)
The tumoral and stromal immune microenvironment in malignant pleural mesothelioma: A comprehensive analysis reveals prognostic immune markers
H. Ujiie (2015)
Regulation of matrix metalloprotease activity in malignant mesothelioma cell lines by growth factors
Z. Liu (2003)
Tumor PD-L1 expression in malignant pleural and peritoneal mesothelioma by Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx assays.
D. Chapel (2019)
Malignant Peritoneal Mesothelioma Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Is GLUT1 Expression a Major Prognostic Factor? A Preliminary Study
J. Hommell-Fontaine (2013)
Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid
A. Scherpereel (2013)
American Thoracic Society International Conference Abstracts: American Thoracic Society
CJ Chapman (2011)
topic: mesothelioma and SCLC
W-S Lam (2017)
A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors.
X. Liu (2016)
High Blood Neutrophil-to-Lymphocyte Ratio Is an Indicator of Poor Prognosis in Malignant Mesothelioma Patients Undergoing Systemic Therapy
S. Kao (2010)
Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells
P. Schuberth (2013)
Pleural Effusion of Patients with Malignant Mesothelioma Induces Macrophage‐Mediated T Cell Suppression
L. Lievense (2016)
Expression and prognostic significance of hypoxia-inducible factor 1α (HIF-1α) in malignant pleural mesothelioma (MPM)
A. Klabatsa (2006)
Local effector failure in mesothelioma is not mediated by CD4+ CD25+ T-regulator cells
C. Jackaman (2009)
Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition.
Leonid Cherkassky (2016)
Hypoxia promotes acquisition of aggressive phenotypes in human malignant mesothelioma
Myung-Chul Kim (2018)
L-type amino acid transporter 1 (LAT1) expression in malignant pleural mesothelioma.
K. Kaira (2011)
Pleural macrophage recruitment and activation in asbestos-induced pleural injury.
N. Choe (1997)
Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis
X. Shen (2018)
CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection
N. Yamada (2010)
Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial
G. Zalcman (2016)
Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial.
G. Scagliotti (2019)
the role of beta1 integrins
J Klominek (1997)
Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma ( KEYNOTE - 028 ) : preliminary results from a non - randomised , open - label , phase 1 b trial
Y Metaxas (2017)
EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors
H. Kothmaier (2007)
This paper is referenced by
Wee1 kinase inhibitor AZD1775 potentiates CD8+ T cell-dependent antitumour activity via dendritic cell activation following a single high dose of irradiation
Bin Wang (2020)
Characterization of the immune microenvironment in malignant pleural mesothelioma reveals prognostic subgroups of patients.
N. Fusco (2020)
Malignant Pleural Mesothelioma: Genetic and Microenviromental Heterogeneity as an Unexpected Reading Frame and Therapeutic Challenge
D. M. Abbott (2020)
The Effects of Asbestos Fibers on Human T Cells
Naoko Kumagai-Takei (2020)
Lactate dehydrogenase-elevating virus enhances natural killer cell-mediated immunosurveillance of mouse mesothelioma development
Mohamed F. Mandour (2020)