Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models

Abstract

Recombinant human erythropoietin (rHuEpo) has been used successfully in the treatment of cancer-related anemia. Clinical observations with several patients with multiple-myeloma treated with rHuEpo has shown, in addition to the improved quality of life, a longer survival than expected, considering the poor prognostic features of these patients. Based on these observations, we evaluated the potential biological effects of rHuEpo on the course of tumor progression by using murine myeloma models (MOPC-315-IgA 2 and 5T33 MM-IgG 2b). Here we report that daily treatment of MOPC-315 tumorbearing mice with rHuEpo for several weeks induced complete tumor regression in 30 -60% of mice. All regressors that were rechallenged with tumor cells rejected tumor growth, and this resistance was tumor specific. The Epo-triggered therapeutic effect was shown to be attributed to a T cell-mediated mechanism. Serum Ig analysis indicated a reduction in MOPC-315 light chain in regressor mice. Intradermal inoculation of 5T33 MM tumor cells followed by Epo treatment induced tumor regression in 60% of mice. The common clinical manifestation of myeloma bone disease in patients with multiple-myeloma was established in these myeloma models. Epo administration to these tumor-bearing mice markedly prolonged their survival and reduced mortality. Therefore, erythropoietin seems to act as an antitumor therapeutic agent in addition to its red blood cell-stimulating activity.

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

“…We centered on DCs as potential candidates that mediate the effects of EPO on lymphocytes, shown in the enhancement of both the cellular and humoral components of the immune system (Katz et al, 2007;Mittelman et al, 2001). Notably, DCs are the most potent APCs and are therefore capable of diverting the entire immune response according to the stimulatory signals that they receive (Katz et al, 2007;Mittelman et al, 2001).…”

“…Notably, DCs are the most potent APCs and are therefore capable of diverting the entire immune response according to the stimulatory signals that they receive (Katz et al, 2007;Mittelman et al, 2001). …”

“…Studies in mouse models of MM lent further support to the concept regarding EPO antineoplastic activity, and indicated that this activity was mediated by the CD8 lymphoid population (Mittelman et al, 2001). More recently we noted EPO effects also on the humoral immune response of antigen-injected mice in both EPO-treated mice and tg6 mice (Ruschitzka et al, 2000;Vogel et al, 2003) -transgenic mice over-expressing human EPO (HuEPO) (Katz et al, 2007).…”

Activities of erythropoietin on tumors: An immunological perspective

“…Previous studies from these authors indicated that EPO may prolong survival in MM patients [8], and these results have been supported by other scientists [9]. The effect of EPO on MM was also reproduced in murine models, where EPO promotes the development of an effective and long-lasting anti-tumor specific immune response mediated via activated CD8 + T cells [10]. By specifically investigating EPO effects on immunological functions in advanced MM patients, a study from the same group showed that EPO increased T cell activation and proliferation, normalized the CD4:CD8 T cell ratio, decreased the percentage of CD8 + T cells expressing the inhibitory molecule CTLA-4, and increased CD8 + T cells expressing the costimulatory CD28 [11].…”

“…The heterogeneity of tumors makes this a very difficult task, and the presence of EPO receptors (EPOR) on tumor cells could be the key factor in determining potentially negative effects in terms of stimulating tumor growth [6]. In this regard, the antitumor effect in MM might be due to the favorable absence of EPOR on MM cells [10]. While analysis of the existing clinical trials have not yet fully clarified this issue [1], a cautionary approach seems advisable.…”