Investigation of sex-biased differences in anti-cancer immune responses

Cancer represents a leading cause of death worldwide and due to demographic change its incidence will strongly increase in the coming decades. Despite novel innovative treatment strategies cancer mortality is still high, especially in advanced disease stages. The introduction of immune checkpoint inhibitors (ICI), which block tumor-elicited inhibitory signals on CD8+ cytotoxic T cells, has revolutionized treatment of cancer patients. Nevertheless, only approximately 20% of patients show long-term benefit. Therefore, there is an urgent need to improve efficacy of cancer immune therapies in order to achieve long-term benefit in more patients. In this context a striking fundamental knowledge gap exists concerning mechanisms of action and efficacy of ICI in males versus females despite the well-documented sex-bias of immune responses. Notably, less than 10% of related publications analyze their data according to the sex of the subjects and a exists a substantial gender imbalance in recent ICB registration trials because considerably more male subjects were treated. For example, in recent Phase 3 registration trials with immune checkpoint inhibitors (ICI) in different entities, approximately 70% of patients were male. These numbers indicate a substantial imbalance in sex which becomes even more alarming because recent meta-analyses point to a higher efficacy of ICI in male patients. We hypothesize that testosterone modulates anti-cancer immune responses and investigate the underlying mechanisms at the functional level using preclinical model systems including co-cultures of tumor and immune cells.

Ben-Batalla, I., M. E. Vargas-Delgado, M. Janning, G. Von Amsberg, and S. Loges. (2020)
Influence of androgens in immunity to self and foreign: Effects on immunity and cancer
Frontiers in Immunology 11:1184

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Ben-Batalla, I., M. E. Vargas-Delgado, L. Meier, and S. Loges. (2019)
Sexual dimorphism in solidand hematological malignancies
Semin Immunopathol 41: 251-263

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Bauer, R., F. Udonta, M. Wroblewski, I. Ben-Batalla, I. M. Santos, F. Taverna, M. Kuhlencord, V. Gensch, S. Pasler, S. Vinckier, J. M. Brandner, K. Pantel, C. Bokemeyer, T. Vogl, J. Roth, P. Carmeliet, and S. Loges. (2018)
Blockade of Myeloid-Derived Suppressor Cell Expansion with All-Trans Retinoic Acid Increases the Efficacy of Antiangiogenic Therapy
Cancer Res 78:3220-3232

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Wroblewski, M., R. Bauer, M. Cubas Cordova, F. Udonta, I. Ben-Batalla, K. Legler, C. Hauser, J. Egberts, M. Janning, J. Velthaus, C. Schulze, K. Pantel, C. Bokemeyer, and S. Loges. (2017)
Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B
Nat Commun 8: 269

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Ben-Batalla, I., R. Erdmann, H. Jorgensen, R. Mitchell, T. Ernst, G. von Amsberg, P. Schafhausen, J. L. Velthaus, S. Rankin, R. E. Clark, S. Koschmieder, A. Schultze, S. Mitra, P. Vandenberghe, T. H. Brummendorf, P. Carmeliet, A. Hochhaus, K. Pantel, C. Bokemeyer, G. V. Helgason, T. L. Holyoake, and S. Loges. (2017)
Axl Blockade by BGB324 Inhibits BCRABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia
Clin Cancer Res 23: 2289-2300

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Waizenegger, J. S., I. Ben-Batalla, N. Weinhold, T. Meissner, M. Wroblewski, M. Janning, K. Riecken, M. Binder, D. Atanackovic, H. Taipaleenmaeki, D. Schewe, S. Sawall, V. Gensch, M. Cubas-Cordova, A. Seckinger, W. Fiedler, E. Hesse, N. Kroger, B. Fehse, D. Hose, B. Klein, M. S. Raab, K. Pantel, C. Bokemeyer, and S. Loges. (2015)
Role of Growth arrestspecific gene 6-Mer axis in multiple myeloma
Leukemia 29: 696-704

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Ben-Batalla, I., A. Schultze, M. Wroblewski, R. Erdmann, M. Heuser, J. S. Waizenegger, K. Riecken, M. Binder, D. Schewe, S. Sawall, V. Witzke, M. Cubas-Cordova, M. Janning, J. Wellbrock, B. Fehse, C. Hagel, J. Krauter, A. Ganser, J. B. Lorens, W. Fiedler, P. Carmeliet, K. Pantel, C. Bokemeyer, and S. Loges. (2013)
Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma
Blood 122: 2443-2452

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Schmidt, T., B. Kharabi Masouleh, S. Loges, S. Cauwenberghs, P. Fraisl, C. Maes, B. Jonckx, K. De Keersmaecker, M. Kleppe, M. Tjwa, T. Schenk, S. Vinckier, R. Fragoso, M. De Mol, K. Beel, S. Dias, C. Verfaillie, R. E. Clark, T. H. Brummendorf, P. Vandenberghe, S. Rafii, T. Holyoake, A. Hochhaus, J. Cools, M. Karin, G. Carmeliet, M. Dewerchin, and P. Carmeliet. (2011)
Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinibresistant Bcr-Abl1(+) leukemia
Cancer Cell 19: 740-753

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Loges, S., T. Schmidt, M. Tjwa, K. van Geyte, D. Lievens, E. Lutgens, D. Vanhoutte, D. Borgel, S. Plaisance, M. Hoylaerts, A. Luttun, M. Dewerchin, B. Jonckx, and P. Carmeliet. (2010)
Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6
Blood 115: 2264-2273

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Loges, S., M. Mazzone, P. Hohensinner, and P. Carmeliet. (2009)
Silencing or fueling metastasiswith VEGF inhibitors: antiangiogenesis revisited
Cancer Cell 15: 167-170

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