[en] [en] BACKGROUND: In mesothelioma (MPM), clinical evidence indicates that the absolute eosinophil count negatively correlates with overall survival and response to standard chemotherapy. Since eosinophils poorly infiltrate MPM tumours, we hypothesised that endocrine rather than paracrine pathways mediate the therapeutic response. We thus studied the effect of eosinophil-associated factors on response to chemotherapy in mesothelioma.
METHODS: The culture supernatant conditioned by primary human eosinophils was added to mesothelioma cells in presence of the standard chemotherapeutic regimen. The effectiveness of an anti-eosinophil treatment was evaluated in a preclinical model of C57BL/6 mice transplanted with mesothelioma tumour cells.
FINDINGS: Supernatant of eosinophils differentiated from EOL1 cells or directly isolated from peripheral blood inhibited apoptosis induced by cisplatin and pemetrexed in 2D cultures and in spheroids. Transcriptomic analysis indicated that the anti-apoptotic effect mediated by eosinophils involved molecular interactions with the Charcot-Leyden Crystal protein or Galectin-10 (CLC-P/Gal10). The functional relevance of CLC-P/Gal10 was demonstrated by antibody-mediated depletion. Recombinant human CLC-P/Gal10 mimicked the anti-apoptotic activity of eosinophil-derived supernatants. In the mouse model, eosinophilia did not significantly affect tumour growth but altered the response to chemotherapy. Finally, pretreatment of eosinophilia with the anti-Siglec-F antibody before chemotherapy restored the effectiveness of the treatment.
INTERPRETATION: This study provides a mechanistic rationale to clinical evidence correlating the poor outcome of patients with mesothelioma and with eosinophil-derived CLC-P/Gal10, opening new prospects for intervention in this fatal solid tumour.
FUNDING: Belgian Foundation against Cancer, Fonds National de la Recherche Scientifique (FNRS), Télévie, Foundation Léon Fredericq, ULiège.
Disciplines :
Oncology
Author, co-author :
Willems, Mégane ✱; Université de Liège - ULiège > GIGA > GIGA Cancer - Cellular and Molecular Epigenetics
Hamaïdia, Malik ✱; Université de Liège - ULiège > Département GxABT > Microbial technologies
Fontaine, Alexis ; Université de Liège - ULiège > TERRA Research Centre
Grégoire, Mélanie ; Université de Liège - ULiège > TERRA Research Centre
Halkin, Louise ; Université de Liège - ULiège > Département GxABT > Microbial technologies
Vilanova Mana, Lea ; Université de Liège - ULiège > GIGA > GIGA Cancer - Cellular and Molecular Epigenetics
Terres, Roxane ; Université de Liège - ULiège > Département GxABT > Microbial technologies
Jamakhani, Majeed ; Université de Liège - ULiège > GIGA > GIGA Cancer - Cellular and Molecular Epigenetics
Deshayes, Sophie; Institut National de la Santé et de la Recherche Médicale (INSERM) U1232 Centre de Recherche en Cancérologie et Immunologie Nantes Angers (CRCINA), Nantes, France
Brostaux, Yves ; Université de Liège - ULiège > TERRA Research Centre > Modélisation et développement
HEINEN, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
LOUIS, Renaud ; Centre Hospitalier Universitaire de Liège - CHU > > Secteur gardiennage
Duysinx, Bernard ; Université de Liège - ULiège > Département des sciences cliniques
Jean, Didier; Centre de Recherche des Cordeliers (INSERM), Sorbonne Université (Université de Paris), Functional Genomics of Solid Tumors, Paris, France
Wasielewski, Eric; Department of Pneumology and Thoracic Oncology (CHU Lille) and INSERM U1189 (ONCOTHAI), Lille, France
Scherpereel, Arnaud; Department of Pneumology and Thoracic Oncology (CHU Lille) and INSERM U1189 (ONCOTHAI), Lille, France
Blanquart, Christophe; Institut National de la Santé et de la Recherche Médicale (INSERM) U1232 Centre de Recherche en Cancérologie et Immunologie Nantes Angers (CRCINA), Nantes, France
Willems, Luc ; Université de Liège - ULiège > GIGA > GIGA Cancer - Cellular and Molecular Epigenetics
Belgian Foundation against Cancer, Fonds National de la Recherche Scientifique (FNRS), T\u00E9l\u00E9vie, Foundation L\u00E9on Fredericq, ULi\u00E8ge.This work was supported by the Belgian Foundation against Cancer (projects FA/2018/1226 and FA/2022/1931), the Foundation L\u00E9on Fredericq (RT-2023, LH-2023, AF-2023), the Fonds National de la Recherche Scientifique (FNRS) and the T\u00E9l\u00E9vie (7.4602.20, 7.4606.21, 7.4610.22). AF and LVM (T\u00E9l\u00E9vie Fellows), LH (research fellow), LW (research director), MJ and MH (postdoctoral researchers) are members of the FNRS. MW and MG were supported by institutional grants. Clinicians are AS and EW (CHU Lille), VH, RL and BD (University Hospital of Liege). We are very grateful to the Red Cross of Belgium for providing the buffy coats. We thank Claire Josse and Christophe Desmet for their advice with mice experiments. We appreciate the valuable help of the GIGA technology platforms, in particular the imaging, genotranscriptomic and animal experimental facilities. We thank H\u00E9l\u00E8ne Hiertz for her experimental contribution on the spheroid model and Jean-Rock Jacques for his technical expertise.This work was supported by the Belgian Foundation against Cancer (projects FA/2018/1226 and FA/2022/1931), the Foundation L\u00E9on Fredericq (RT-2023, LH-2023, AF-2023), the Fonds National de la Recherche Scientifique (FNRS) and the T\u00E9l\u00E9vie (7.4602.20, 7.4606.21, 7.4610.22). AF and LVM (T\u00E9l\u00E9vie Fellows), LH (research fellow), LW (research director), MJ and MH (postdoctoral researchers) are members of the FNRS. MW and MG were supported by institutional grants. Clinicians are AS and EW (CHU Lille), VH, RL and BD (University Hospital of Liege).
Asciak, R., George, V., Rahman, N.M., Update on biology and management of mesothelioma. Eur Respir Rev, 30, 2021, 200226.
Alpert, N., Gerwen, M van, Taioli, E., Epidemiology of mesothelioma in the 21st century in Europe and the United States, 40 years after restricted/banned asbestos use. Transl Lung Cancer Res 9 (2020), S28–S38.
Pira, E., Godono, A., Ciocan, C., Novel issues in the epidemiology of asbestos-related diseases. Curr Opin Epidemiol Public Health 1 (2022), 4–10.
Vogelzang, N.J., Rusthoven, J.J., Symanowski, J., et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21 (2003), 2636–2644.
Zalcman, G., Mazieres, J., Margery, J., et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387 (2016), 1405–1414.
Baas, P., Scherpereel, A., Nowak, A.K., et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet 397 (2021), 375–386.
Popat, S., Baas, P., Faivre-Finn, C., et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 33 (2022), 129–142.
Oehl, K., Vrugt, B., Opitz, I., Meerang, M., Heterogeneity in malignant pleural mesothelioma. Int J Mol Sci, 19, 2018, 1603.
Minnema-Luiting, J., Vroman, H., Aerts, J., Cornelissen, R., Heterogeneity in immune cell content in malignant pleural mesothelioma. Int J Mol Sci, 19, 2018, 1041.
Mola, S., Pinton, G., Erreni, M., et al. Inhibition of the histone methyltransferase EZH2 enhances protumor monocyte recruitment in human mesothelioma spheroids. Int J Mol Sci, 22, 2021, 4391.
Mossman, B.T., Shukla, A., Heintz, N.H., Verschraegen, C.F., Thomas, A., Hassan, R., New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas. Am J Pathol 182 (2013), 1065–1077.
Yap, T.A., Aerts, J.G., Popat, S., Fennell, D.A., Novel insights into mesothelioma biology and implications for therapy. Nat Rev Cancer 17 (2017), 475–488.
Chéné, A.-L., 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 11 (2016), 1765–1773.
Lievense, L.A., Cornelissen, R., Bezemer, K., Kaijen-Lambers, M.E.H., Hegmans, J.P.J.J., Aerts, J.G.J.V., Pleural effusion of patients with malignant mesothelioma induces macrophage-mediated T cell suppression. J Thorac Oncol 11 (2016), 1755–1764.
Gauttier, V., Pengam, S., Durand, J., et al. Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance. J Clin Invest 130 (2020), 6109–6123.
Hiltbrunner, S., Mannarino, L., Kirschner, M.B., et al. Tumor immune microenvironment and genetic alterations in mesothelioma. Front Oncol, 11, 2021, 660039.
Hoyos, C., Fontaine, A., Jacques, J.-R., et al. HDAC inhibition with valproate improves direct cytotoxicity of monocytes against mesothelioma tumor cells. Cancers, 14, 2022, 2164.
Hamaidia, M., Gazon, H., Hoyos, C., et al. Inhibition of EZH2 methyltransferase decreases immunoediting of mesothelioma cells by autologous macrophages through a PD-1-dependent mechanism. JCI Insight, 4, 2019, e128474.
Chu, G.J., van Zandwijk, N., Rasko, J.E.J., The immune microenvironment in mesothelioma: mechanisms of resistance to immunotherapy. Front Oncol, 9, 2019, 1366.
Cersosimo, F., Barbarino, M., Lonardi, S., et al. Mesothelioma malignancy and the microenvironment: molecular mechanisms. Cancers, 13, 2021, 5664.
Wu, L., Kohno, M., Murakami, J., et al. Defining and targeting tumor-associated macrophages in malignant mesothelioma. Proc Natl Acad Sci U S A, 120, 2023, e2210836120.
Cimen, F., Agackiran, Y., Düzgün, S., Aloglu, M., Senturk, A., Atikcan, S., Factors affecting the life expectancy in malignant pleural mesothelioma: our 10 years of studies and experience. Medicine, 101, 2022, e30711.
Fournel, L., Charrier, T., Huriet, M., et al. Prognostic impact of inflammation in malignant pleural mesothelioma: a large-scale analysis of consecutive patients. Lung Cancer 166 (2022), 221–227.
Okita, R., Okada, M., Inokawa, H., Murakami, T., Ikeda, E., Prognostic values of preoperative C-reactive protein, albumin, and neutrophil ratios in patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy. Surg Oncol, 43, 2022, 101813.
Willems, M., Scherpereel, A., Wasielewski, E., et al. Excess of blood eosinophils prior to therapy correlates with worse prognosis in mesothelioma. Front Immunol, 14, 2023, 1148798.
Rothenberg, M.E., Hogan, S.P., The eosinophil. Annu Rev Immunol 24 (2006), 147–174.
Kovalszki, A., Weller, P.F., Eosinophils and eosinophilia. Rich, R.R., Fleisher, T.A., Shearer, W.T., Schroeder, H.W., Frew, A., Weyand, C.M., (eds.) Clinical immunology, 2019, Elsevier, 349–361.e1.
Grisaru-Tal, S., Itan, M., Klion, A.D., Munitz, A., A new dawn for eosinophils in the tumour microenvironment. Nat Rev Cancer 20 (2020), 594–607.
Reichman, H., Karo-Atar, D., Munitz, A., Emerging roles for eosinophils in the tumor microenvironment. Trends Cancer 2 (2016), 664–675.
Sibille, A., Corhay, J.-L., Louis, R., Ninane, V., Jerusalem, G., Duysinx, B., Eosinophils and lung cancer: from bench to bedside. Int J Mol Sci, 23, 2022, 5066.
Simon, S.C.S., Utikal, J., Umansky, V., Opposing roles of eosinophils in cancer. Cancer Immunol Immunother 68 (2019), 823–833.
Akuthota, P., Wang, H.B., Spencer, L.A., Weller, P.F., Immunoregulatory roles of eosinophils: a new look at a familiar cell. Clin Exp Allergy 38 (2008), 1254–1263.
Kovalszki, A., Weller, P.F., Eosinophilia. Prim Care Clin Off Pract 43 (2016), 607–617.
Adamko, D.J., Wu, Y., Gleich, G.J., Lacy, P., Moqbel, R., The induction of eosinophil peroxidase release: improved methods of measurement and stimulation. J Immunol Methods 291 (2004), 101–108.
Quetel, L., Meiller, C., Assié, J.B., et al. Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival. Mol Oncol 14 (2020), 1207–1223.
Blum, Y., Meiller, C., Quetel, L., et al. Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications. Nat Commun, 10, 2019, 10.1038/s41467-019-09307-6.
Friedrich, J., Seidel, C., Ebner, R., Kunz-Schughart, L.A., Spheroid-based drug screen: considerations and practical approach. Nat Protoc 4 (2009), 309–324.
Gueugnon, F., Leclercq, S., Blanquart, C., et al. Identification of novel markers for the diagnosis of malignant pleural mesothelioma. Am J Pathol 178 (2011), 1033–1042.
Reimand, J., Kull, M., Peterson, H., Hansen, J., Vilo, J., g:Profiler--a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res 35 (2007), W193–W200.
Wu, T., Hu, E., Xu, S., et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation, 2, 2021, 100141.
Tomizawa, H., Yamada, Y., Arima, M., et al. Galectin-10 as a potential biomarker for eosinophilic diseases. Biomolecules, 12, 2022, 1385.
Klion, A.D., Ackerman, S.J., Bochner, B.S., Contributions of eosinophils to human health and disease. Annu Rev Pathol 15 (2020), 179–209.
Canino, C., Mori, F., Cambria, A., et al. SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells. Oncogene 31 (2012), 3148–3163.
Guillon, J., Petit, C., Toutain, B., Guette, C., Lelièvre, E., Coqueret, O., Chemotherapy-induced senescence, an adaptive mechanism driving resistance and tumor heterogeneity. Cell Cycle 18 (2019), 2385–2397.
Hegmans, J.P.J.J., Hemmes, A., Hammad, H., Boon, L., Hoogsteden, H.C., Lambrecht, B.N., Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. Eur Respir J 27 (2006), 1086–1095.
Cordier Kellerman, L., Valeyrie, L., Fernandez, N., et al. Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma. Cancer Gene Ther 10 (2003), 481–490.
Johnston, L.K., Bryce, P.J., Understanding interleukin 33 and its roles in eosinophil development. Front Med, 4, 2017, 51.
Salaroglio, I.C., Kopecka, J., Napoli, F., et al. Potential diagnostic and prognostic role of microenvironment in malignant pleural mesothelioma. J Thorac Oncol 14 (2019), 1458–1471.
De Fonseka, D., Arnold, D.T., Morley, A.J., et al. Lymphocyte predominance in blood, pleural fluid, and tumour stroma; a prognostic marker in pleural mesothelioma. BMC Pulm Med, 22, 2022, 173.
Wang, L., Lankhorst, L., Bernards, R., Exploiting senescence for the treatment of cancer. Nat Rev Cancer 22 (2022), 340–355.
Oehl, K., Kresoja-Rakic, J., Opitz, I., et al. Live-cell mesothelioma biobank to explore mechanisms of tumor progression. Front Oncol, 8, 2018, 40.
Sidi, R., Pasello, G., Opitz, I., et al. Induction of senescence markers after neo-adjuvant chemotherapy of malignant pleural mesothelioma and association with clinical outcome: an exploratory analysis. Eur J Cancer 47 (2011), 326–332.
Weller, P.F., Wang, H., Melo, R.C.N., The Charcot–Leyden crystal protein revisited—a lysopalmitoylphospholipase and more. J Leukoc Biol 108 (2020), 105–112.
Ackerman, S.J., Liu, L., Kwatia, M.A., et al. Charcot-leyden crystal protein (Galectin-10) is not a dual function galectin with lysophospholipase activity but binds a lysophospholipase inhibitor in a novel structural fashion. J Biol Chem 277 (2002), 14859–14868.
Su, J., A brief history of charcot-leyden crystal protein/galectin-10 research. Molecules, 23, 2018, 2931.
Ueki, S., Miyabe, Y., Yamamoto, Y., et al. Charcot-leyden crystals in eosinophilic inflammation: active cytolysis leads to crystal formation. Curr Allergy Asthma Rep, 19, 2019, 38.
Persson, E.K., Verstraete, K., Heyndrickx, I., et al. Protein crystallization promotes type 2 immunity and is reversible by antibody treatment. Science, 364, 2019, eaaw4295.
Fukuchi, M., Kamide, Y., Ueki, S., et al. Eosinophil ETosis–mediated release of galectin-10 in eosinophilic granulomatosis with polyangiitis. Arthritis Rheumatol 73 (2021), 1683–1693.
Ueki, S., Tokunaga, T., Melo, R.C.N., et al. Charcot-Leyden crystal formation is closely associated with eosinophil extracellular trap cell death. Blood 132 (2018), 2183–2187.
Stockhammer, P., Ploenes, T., Theegarten, D., et al. Detection of TGF-β in pleural effusions for diagnosis and prognostic stratification of malignant pleural mesothelioma. Lung Cancer 139 (2020), 124–132.
Kirschner, M.B., Pulford, E., Hoda, M.A., et al. Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis. Br J Cancer 113 (2015), 963–969.
Byrne, M.J., Nowak, A.K., Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 15 (2004), 257–260.
Staumont, B., Jamakhani, M., Costa, C., et al. TGFα promotes chemoresistance of malignant pleural mesothelioma. Cancers, 12, 2020, 1484.
Cusack, R.P., Whetstone, C.E., Xie, Y., Ranjbar, M., Gauvreau, G.M., Regulation of eosinophilia in asthma—new therapeutic approaches for asthma treatment. Cells, 10, 2021, 817.
Dellon, E.S., Peterson, K.A., Murray, J.A., et al. Anti–Siglec-8 antibody for eosinophilic gastritis and duodenitis. N Engl J Med 383 (2020), 1624–1634.
