Iron Supplementation Interferes With Immune Therapy of Murine Mammary Carcinoma by Inhibiting Anti-Tumor T Cell Function

Abstract

Iron is both, an essential compound for many metabolic processes, and iron deficiency can impact on the proliferation of cells including lymphocytes but also tumor cells. On the other hand, excess iron-catalyzed radical formation can induce cellular toxicity which has been previously demonstrated for T cells in hereditary iron overload. Despite these interconnections, little is known on the effects of clinically approved intravenous iron supplements for curing cancer-related anemia, on T cell differentiation, tumor proliferation, anti-tumor T cell responses and, of clinical importance, on efficacy of cancer immunotherapies. Herein, we analyzed the effects of intravenous iron supplementation on T cell function and on the effectiveness of anti-cancer chemotherapy with IL-2/doxorubicin or immunotherapy with checkpoint-inhibitor anti-PD-L1 in C57Bl/6N female mice with implanted E0771 mammary carcinomas. We found that iron application resulted to an increased availability of iron in the tumor microenvironment and stimulation of tumor growth. In parallel, iron application inhibited the activation, expansion and survival of cytotoxic CD8+ T cells and of CD4+ T helper cells type 1 and significantly reduced the efficacy of the investigated anti-cancer treatments. Our results indicate that iron administration has a tumor growth promoting effect and impairs anti-cancer responses of tumor infiltrating T lymphocytes along with a reduced efficacy of anti-cancer therapies. Iron supplementation in cancer patients, especially in those treated with immunotherapies in a curative setting, may be thus used cautiously and prospective studies have to clarify the impact of such intervention on the outcome of patients.