Erythropoietin induces tumour progression and CD39 expression on immune cells in a preclinical model of triple-negative breast cancer

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.