Hypothermic microenvironment plays a key role in tumor immune subversion.

There are diverse immunosuppressive factors in the tumor microenvironment, but the main reason for these factors is unclear. Because hypothermia induces micronuclei in mouse bone marrow cells and because alterations in body temperature may influence immune system function, we aimed to investigate whether the hypothermic microenvironment is associated with the presence of diverse immunosuppressive factors. We found that hypothermic culture (34°C) decreased lymphocyte proliferation, cytotoxic CD8+ T cell function and Th1 cell expression of IFN-γ and IL-2 in vitro, with a concomitant increase in Th2 and Treg cell populations. Whole-body hypothermia at a temperature less than 34°C produced an immunosuppressive microenvironment, resulting in an increase in splenic Treg and Th2 cell populations as well as increased serum IL-4 and IL-10 levels in vivo. As a result of whole-body hypothermia, less than one of two cells in a conventional syngeneic tumor model was capable of tumor formation. In contrast, febrile-range hyperthermia (39-40°C) promoted a T cell-mediated immune response, resulting in an increase in splenic Th1 and Tc1 cell populations, which caused more than a two-fold increase in the number of nontumorigenic cells in a conventional syngeneic tumor model. Similarly, local hypothermia induced by microcirculatory dysfunction or the application of a cold compress increased intratumor Treg cells and TGF-β1 levels, which promote lung metastasis, whereas local hyperthermia induced by capsaicin stimulation or a hot compress had the opposite effect. These results confirmed the hypothesis that tumor hypothermia determines the immunosuppressive microenvironment and suggested a novel treatment strategy for solid tumors.