Erythropoietin improves antitumor immune response through reversal of the hypoxic tumor microenvironment
Mentor: Michail Sitkovsky, PhD (Northeastern University)
Erythropoietin (Epo), a widely used glycoprotein, aids in the increase of red blood cell production. Epo is a cytokine- a cell-signaling molecule that stimulates hematopoietic stem cells to produce more red blood cells. In addition to its use as treatment for anemia, administration of Epo to mice has resulted in tumor regression. Cancerous tumors facilitate a hypoxic environment, which in turn supports their growth, as well as the suppression of tumor killing immune cells. The creation of adenosine and low oxygen tensions drive immunosuppression within the tumor microenvironment. In hypoxic conditions, various factors regulate and promote accumulation of adenosine in the hypoxic environment, which suppresses the release of cytokines from immune cells. In hypoxic conditions, the A2A receptor increases cAMP, resulting in increased adenosine signaling. Adenosine suppresses the release of cytokines from immune cells. Extracellular enzymes, CD39 and CD73 promote the antitumor environment by dephosphorylating ADP and AMP to create adenosine outside of the cell. In hypoxic conditions, Epo increases the hemoglobin in red blood cells, better enabling the delivery of oxygen to hypoxic areas. We will examine the ability of Epo to enable immune cell driven tumor regression through the delivery of oxygen to hypoxic tumor environments. In previous studies, administration of erythropoietin has been proven to cause tumor regression in 60% of mice with multiple myeloma MOPC-315 tumors. It has been shown that the presence of Epo aids in the recruitment of CD8+ T-cells to tumor sites, but the direct relationship between Epo and immune cells has yet to be explored. We hope to analyze the direct effects of erythropoietin on specific groups of immune cells using MCA-205 fibrosarcoma tumors in mice models as a means for improving the antitumor immune response.
Low levels of oxygen within tumors are thought to inhibit the T-cell response against tumor cells. We hypothesize that increasing local oxygen tension will reverse this process and thereby aid in the immunosuppression of tumor growth. Source: Sitkovsky et al. Nature Reviews Immunology 2005;5:712-721 Source: