ABSTRACT
The adverse effects observed in some cancer patients treated with erythropoiesis-stimulating agents such as erythropoietin (EPO) might be due to the latter's well-known immunosuppressive functions. Here, we used a mouse model of syngeneic triple-negative breast cancer to explore EPO's immunomodulatory role in a tumour setting. Our results showed that EPO treatment promotes tumour growth, exacerbates the 'immune desert', and results in a 'cold tumour'. EPO treatment changed the immune cell distribution in peripheral blood, secondary lymphoid organs, and the tumour microenvironment (TME). Our in-depth analysis showed that EPO mainly impacts CD4 T cells by accelerating their activation in the spleen and thus their subsequent exhaustion in the TME. This process is accompanied by a general elevation of CD39 expression by several immune cells (notably CD4 T cells in the tumour and spleen), which promotes an immunosuppressive TME. Lastly, we identified a highly immunosuppressive CD39+ regulatory T cell population (ICOS+, CTLA4+, Ki67+) as a potential biomarker of the risk of EPO-induced tumour progression. EPO displays pleiotropic immunosuppressive functions and enhances mammary tumour progression in mice.
Subject(s)
Betacoronavirus/isolation & purification , Chilblains/diagnosis , Coronavirus Infections/complications , Lupus Erythematosus, Cutaneous/diagnosis , Pneumonia, Viral/complications , Adult , Betacoronavirus/genetics , Betacoronavirus/immunology , COVID-19 , COVID-19 Testing , Chilblains/epidemiology , Chilblains/immunology , Chilblains/virology , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/virology , Diagnosis, Differential , Female , Humans , Interferon Type I/blood , Interferon Type I/immunology , Lupus Erythematosus, Cutaneous/epidemiology , Lupus Erythematosus, Cutaneous/immunology , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , RNA, Viral/isolation & purification , Risk Factors , SARS-CoV-2ABSTRACT
Thrombopoietin (TPO), through activation of its cognate receptor Mpl, is the major regulator of platelet production. However, residual platelets observed in TPO- and Mpl-loss-of-function (LOF) mice suggest the existence of an additional factor to TPO in platelet production. As erythropoietin (EPO) exhibited both in vitro megakaryocytic potential, in association with other early-acting cytokines, and in vivo platelet activation activity, we sought to investigate its role in this setting. Here, we used multiple LOF models to decipher the reciprocal role of EPO and TPO in the regulation of platelet production in TPO-LOF and Mpl-LOF mice and of platelet size heterogeneity in wild-type mice. We first identified EPO as the major thrombopoietic factor in the absence of the TPO-Mpl pathway. Based on the study of several mouse models we found that the EPO-EPO receptor pathway acts on late-stage megakaryopoiesis and is responsible for large-sized platelet production, while the TPO-Mpl pathway promotes small-sized platelet production. On the basis of our data, EPO might be used for thrombocytopenia supportive therapy in congenital amegakaryocytopoiesis. Furthermore, as a distribution skewed toward large platelets is an independent risk factor and a poor prognosis indicator in atherothrombosis, the characterization of EPO's role in the production of large-sized platelets, if confirmed in humans, may open new perspectives in the understanding of the role of EPO-induced platelets in atherothrombosis.
Subject(s)
Blood Platelets/metabolism , Erythropoietin/metabolism , Megakaryocytes/microbiology , Thrombopoiesis , Thrombopoietin/metabolism , Animals , Erythropoietin/genetics , Female , Mice , Mice, Knockout , Thrombopoietin/geneticsABSTRACT
Most diseases have multifactorial origins and their study requires complex in vivo validation strategies selected for their particular relevance. Most of the in vivo models used to date have been selected according to their availability and the accessibility of the corresponding technology platform. With the rapid development of new technologies, an increasing number of relevant systems for in vivo target validation are now available. In this review, we present in vivo loss-of-function tools acting at three biological levels (the gene, the messenger RNA and the protein); we discuss the specificity of each strategy and how the three techniques can be combined during the validation process in order to overcome the limitations of each one. Thus, combination will broaden the spectrum of the available validation systems and will enable target validation that predicts the situation in humans as accurately as possible.