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Current Drug Targets


ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

General Review Article

Progress in the Understanding of the Immune Microenvironment and Immunotherapy in Malignant Pleural Mesothelioma

Author(s): Lei Cheng, Na Li, Xiao-ling Xu* and Wei-Min Mao*

Volume 21 , Issue 15 , 2020

Page: [1606 - 1612] Pages: 7

DOI: 10.2174/1389450121666200719011234

Price: $65


Malignant pleural mesothelioma (MPM) is a remarkably aggressive thoracic malignancy with a limited survival of only 5-12 months. However, MPM still remains unresponsive to conventional standards of treatment, including pleurectomy and decortication, extrapleural pneumonectomy for resectable disease with or without chemotherapy, and/or radiation therapy. The mechanism of carcinogenesis has not been fully elucidated, although approximately 80% of cases can still be linked to asbestos exposure. The tumor immune microenvironment (TME) has been proven to play an important role in MPM pathogenesis and treatment outcomes. Several molecular pathways have been implicated in the MPM tumor microenvironment, such as angiogenesis, apoptosis, cell cycle regulation, and stromal processes. Immunotherapy has already shown promising results in other thoracic solid tumors, such as non-small-cell lung cancer (NSCLC). However, immunotherapy has shown less convincing results in MPM than in melanoma and NSCLC. A multicenter, randomized trial (DETERMINE) proved that immune checkpoint inhibition using tremelimumab, an anti-cytotoxic T lymphocyteassociated protein 4 (CTLA-4) antibody, failed to improve median overall survival. Therefore, it is important to explore the relationship between the characteristics of the tumor microenvironment and immunotherapy. Here, we review the heterogeneity of the TME and the progress in the understanding of the immune microenvironment and immunotherapy in MPM to explore the mechanisms of resistance to immunotherapy.

Keywords: Malignant Pleural Mesothelioma (MPM), Tumor Immune Microenvironment (TME), heterogeneity, immunotherapy, molecular pathways, Non-Small-Cell Lung Cancer (NSCLC).

Graphical Abstract
Woolhouse I, Bishop L, Darlison L, et al. British thoracic society guideline for the investigation and management of malignant pleural mesothelioma. Thorax 2018; 73(Suppl. 1): i1-i30.
[] [PMID: 29444986]
Zalcman G, Mazieres J, Margery J, et al. French cooperative thoracic intergroup (IFCT). Bevacizumab for newly diagnosed pleural mesothelioma in the mesothelioma avastin cisplatin pemetrexed study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 2016; 387(10026): 1405-14.
[] [PMID: 26719230]
Grosso F, Scagliotti GV. Systemic treatment of malignant pleural mesothelioma. Future Oncol 2012; 8(3): 293-305.
[] [PMID: 22409465]
Panou V, Vyberg M, Weinreich UM, Meristoudis C, Falkmer UG, Røe OD. The established and future biomarkers of malignant pleural mesothelioma. Cancer Treat Rev 2015; 41(6): 486-95.
[] [PMID: 25979846]
Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. Introduction to the 2015 World Health Organization classification of tumors of the lung, pleura, thymus, and heart. J Thorac Oncol 2015; 10(9): 1240-2.
[] [PMID: 26291007]
Jahan T, Gu L, Kratzke R, et al. Vatalanib in malignant mesothelioma: a phase II trial by the cancer and leukemia group B (CALGB 30107). Lung Cancer 2012; 76(3): 393-6.
[] [PMID: 22197613]
Carbone M, Yang H. Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma. Clinical cancer research : an official journal of the american association for cancer research 2012; 18(3): 598-604.
Bograd AJ, Suzuki K, Vertes E, et al. Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma. Cancer Immunol Immunother 2011; 60(11): 1509-27.
[] [PMID: 21913025]
Jhung MA, Davidson H, McIntyre A, et al. Preliminary results of 2009 pandemic influenza surveillance in the United States using the aggregate hospitalization and death reporting activity. Influenza Other Respir Viruses 2011; 5(5): 321-7.
[] [PMID: 21668693]
Carbone M, Ly BH, Dodson RF, et al. Malignant mesothelioma: facts, myths, and hypotheses. J Cell Physiol 2012; 227(1): 44-58.
[] [PMID: 21412769]
Hegmans JP, Hemmes A, Hammad H, Boon L, Hoogsteden HC, Lambrecht BN. Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. Eur Respir J 2006; 27(6): 1086-95.
[] [PMID: 16540497]
Hegmans JP, Aerts JG. Immunomodulation in cancer. Curr Opin Pharmacol 2014; 17: 17-21.
[] [PMID: 25011112]
Mossman BT, Shukla A, Heintz NH, Verschraegen CF, Thomas A, Hassan R. New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas. Am J Pathol 2013; 182(4): 1065-77.
[] [PMID: 23395095]
Yap TA, Aerts JG, Popat S, Fennell DA. Novel insights into mesothelioma biology and implications for therapy. Nat Rev Cancer 2017; 17(8): 475-88.
[] [PMID: 28740119]
Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001; 17411(6835): 375-9.
Lo A, Wang LS, Scholler J, et al. Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells. Cancer Res 2015; 75(14): 2800-10.
[] [PMID: 25979873]
Egeblad M, Littlepage LE, Werb Z. The fibroblastic coconspirator in cancer progression. Cold Spring Harb Symp Quant Biol 2005; 70: 383-8.
[] [PMID: 16869775]
Li Q, Wang W, Yamada T, et al. Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network. Am J Pathol 2011; 179(3): 1483-93.
[] [PMID: 21763682]
Wang LC, Lo A, Scholler J, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res 2014; 2(2): 154-66.
[] [PMID: 24778279]
Elliott LA, Doherty GA, Sheahan K, Ryan EJ. Human tumorinfiltrating myeloid cells Phenotypic and functional diversity front immunol 2017; 8: 86.
[] [PMID: 28220123]
Veltman JD, Lambers ME, van Nimwegen M, et al. COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. BMC Cancer 2010; 10: 464.
[] [PMID: 20804550]
Burt BM, Rodig SJ, Tilleman TR, Elbardissi AW, Bueno R, Sugarbaker DJ. Circulating and tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma. Cancer 2011; 117(22): 5234-44.
[] [PMID: 21523763]
Cornelissen R, Lievense LA, Maat AP, et al. Ratio of intratumoral macrophage phenotypes is a prognostic factor in epithelioid malignant pleural mesothelioma. PLoS One 2014; 9(9)e106742
[] [PMID: 25192022]
Cornelissen R, Lievense LA, Robertus JL, et al. Intratumoral macrophage phenotype and CD8+ T lymphocytes as potential tools to predict local tumor outgrowth at the intervention site in malignant pleural mesothelioma. Lung Cancer 2015; 88(3): 332-7.
[] [PMID: 25843042]
Chéné AL, d’Almeida S, Blondy T, et al. Pleural effusions from patients with mesothelioma induce recruitment of monocytes and their differentiation into M2 macrophages. J Thorac Oncol 2016; 11(10): 1765-73.
[] [PMID: 27418105]
Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015; 523(7559): 231-5.
[] [PMID: 25970248]
Belderbos RA, Baas P, Berardi R, et al. A multicenter, randomized, phase II/III study of dendritic cells loaded with allogeneic tumor cell lysate (MesoPher) in subjects with mesothelioma as maintenance therapy after chemotherapy: DENdritic cell Immunotherapy for Mesothelioma (DENIM) trial. Transl Lung Cancer Res 2019; 8(3): 280-5.
[] [PMID: 31367541]
Noordam L, Kaijen MEH, Bezemer K, et al. Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy. OncoImmunology 2018; 7(12)e1474318
[] [PMID: 30524884]
Kumagai-Takei N, Nishimura Y, Maeda M, et al. Effect of asbestos exposure on differentiation of cytotoxic T lymphocytes in mixed lymphocyte reaction of human peripheral blood mononuclear cells. Am J Respir Cell Mol Biol 2013; 49(1): 28-36.
[] [PMID: 23449737]
Matsuzaki H, Maeda M, Lee S, et al. Asbestos-induced cellular and molecular alteration of immunocompetent cells and their relationship with chronic inflammation and carcinogenesis. J Biomed Biotechnol 2012.2012492608
[] [PMID: 22500091]
Maeda M, Nishimura Y, Hayashi H, et al. Reduction of CXC chemokine receptor 3 in an in vitro model of continuous exposure to asbestos in a human T-cell line, MT-2. Am J Respir Cell Mol Biol 2011; 45(3): 470-9.
[] [PMID: 21148743]
Xu W, Hiếu T, Malarkannan S, Wang L. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018; 15(5): 438-46.
[] [PMID: 29375120]
Zhai L, Ladomersky E, Lenzen A, et al. IDO1 in cancer: a Gemini of immune checkpoints. Cell Mol Immunol 2018; 15(5): 447-57.
[] [PMID: 29375124]
Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 2005; 5(4): 296-306.
[] [PMID: 15803149]
Sottile R, Tannazi M, Johansson MH, Cristiani CM, Calabro L, Ventura V, et al. NK- and T-cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti-CTLA-4 therapy. Int J Cancer 2019; 145(8): 2238-48.
Wang X, Rivière I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol Ther Oncolytics 2016; 3: 16015.
[] [PMID: 27347557]
Zhang Q, Bi J, Zheng X, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol 2018; 19(7): 723-32.
[] [PMID: 29915296]
Liu Y, Zheng J, Liu Y, et al. Uncompromised NK cell activation is essential for virus-specific CTL activity during acute influenza virus infection. Cell Mol Immunol 2018; 15(9): 827-37.
[] [PMID: 28413216]
Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009; 30(6): 899-911.
[] [PMID: 19464196]
McCoy MJ, Nowak AK, van der Most RG, Dick IM, Lake RA. Peripheral CD8(+) T cell proliferation is prognostic for patients with advanced thoracic malignancies. Cancer Immunol Immunother 2013; 62(3): 529-39.
[] [PMID: 23069871]
Anraku M, Cunningham KS, Yun Z, et al. Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2008; 135(4): 823-9.
[] [PMID: 18374762]
Wei SC, Levine JH, Cogdill AP, et al. Distinct cellular mechanisms underlie Anti-CTLA-4 and Anti-PD-1 checkpoint blockade. Cell 2017; 170(6): 1120-1133.e17.
[] [PMID: 28803728]
杜雪梅 , 李鑫宝 , 于洋 , 孙萍萍 , 高颖 , 昌红 , et al. 恶性间皮瘤中PD-1和PD-L1的表达及意义 %J 临床与实验病理学杂志 %J Chinese Journal of Clinical and Experimental Pathology 2018; 34(12): 1348-52.
[] [PMID: 20128778]
Pasello G, Zago G, Lunardi F, et al. Malignant pleural mesothelioma immune microenvironment and checkpoint expression: correlation with clinical-pathological features and intratumor heterogeneity over time. Ann Oncol 2018; 29(5): 1258-65.
[] [PMID: 29514216]
Metaxas Y, Rivalland G, Mauti LA, et al. Pembrolizumab as palliative immunotherapy in malignant pleural mesothelioma. J Thorac Oncol 2018; 13(11): 1784-91.
[] [PMID: 30142389]
Nguyen BH, Montgomery R, Fadia M, Wang J, Ali S. PD-L1 expression associated with worse survival outcome in malignant pleural mesothelioma. Asia Pac J Clin Oncol 2018; 14(1): 69-73.
[] [PMID: 29105302]
Brosseau S, Danel C, Scherpereel A, et al. Shorter survival in malignant pleural mesothelioma patients with high PD-L1 expression associated with sarcomatoid or biphasic histology subtype: A series of 214 cases from the Bio-MAPS cohort. Clin Lung Cancer 2019; 20(5): e564-75.
[] [PMID: 31279641]
Bronte G, Delmonte A, Burgio MA, et al. Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement. Lung Cancer 2020; 142: 47-50.
[] [PMID: 32088605]
Lee HS, Jang HJ, Choi JM, et al. Comprehensive immunoproteogenomic analyses of malignant pleural mesothelioma. JCI Insight 2018; 3(7): 98575.
[] [PMID: 29618661]

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