Extracellular Ubiquitin is the Causal Link between Stored Blood Transfusion Therapy and Tumor Progression in a Melanoma Mouse Model

Background: The transfusion of blood that has been stored for some time was found to be associated with transfusion-related immune modulation (TRIM) responses in cancer patients, which could result in poor clinical outcomes, such as tumor recurrence, metastasis and reduced survival rate. Given the prior observation of the positive correlation between ubiquitin content in whole blood and storage duration by the investigators of the present study, it was hypothesized that this could be the causal link behind the association between the transfusion of stored blood and poor cancer prognosis. Methods: In the present study, a melanoma mouse model was used to study the potential clinical impact of ubiquitin present in stored blood on cancer prognosis through a variety of cell biology methods, such as flow cytometry and immunohistochemistry. Results: Both extracellular ubiquitin and the infusion of stored mice blood that comprised of ubiquitin reduced the apoptotic rate of melanoma cells, promoted lung tumor metastasis and tumor progression, and reduced the long-term survival rate of melanoma mice. In addition, the upregulation of tumor markers and tumorigenic TH2 cytokine generation, as well as reduced immune cell numbers, were observed in the presence of ubiquitin. Conclusions: The present findings provide novel insights into the role of ubiquitin in immune regulation in a melanoma mouse model, and suggest ubiquitin as the causal link between allogeneic blood transfusion therapy and poor cancer prognosis.