Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature

Abstract

We show here that fundamental aspects of antitumor immunity in mice are significantly influenced by ambient housing temperature. Standard housing temperature for laboratory mice in research facilities is mandated to be between 20-26°C; however, these subthermoneutral temperatures cause mild chronic cold stress, activating thermogenesis to maintain normal body temperature. When stress is alleviated by housing at thermoneutral ambient temperature (30-31°C), we observe a striking reduction in tumor formation, growth rate and metastasis. This improved control of tumor growth is dependent upon the adaptive immune system. We observe significantly increased numbers of antigen-specific CD8 + T lymphocytes and CD8 + T cells with an activated phenotype in the tumor microenvironment at thermoneutrality. At the same time there is a significant reduction in numbers of immunosuppressive MDSCs and regulatory T lymphocytes. Notably, in temperature preference studies, tumor-bearing mice select a higher ambient temperature than non-tumor-bearing mice, suggesting that tumor-bearing mice experience a greater degree of coldstress. Overall, our data raise the hypothesis that suppression of antitumor immunity is an outcome of cold stress-induced thermogenesis. Therefore, the common approach of studying immunity against tumors in mice housed only at standard room temperature may be limiting our understanding of the full potential of the antitumor immune response. murine tumor models | metabolism

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

“…Housing in relatively cold environments, particularly when animals are individually housed (as is common for cachexia studies), leads to a variety of stress responses and overt changes in inflammation and immune function 66. For example, mice demonstrate altered behavioural and immune responses to lipopolysaccharide and have altered tumour growth and anti‐tumour immune responses when housed in sub‐thermoneutral environments 67, 68. For these reasons, the KPC model was characterized with cage temperatures measured at 26°C and with adequate materials (nestlets) for thermoregulation.…”

Thermoneutrality, Mice, and Cancer: A Heated Opinion

“…We recently compared tumor growth at ST and TT in several syngeneic and carcinogen-induced murine tumor models and found that tumors grow significantly more slowly when mice are housed at TT instead of ST [42]. In addition, spontaneous lung metastases of 4T1 were also significantly reduced in mice at TT.…”

“…In our experiments, we currently place cages within incubators (Thermo Fisher Scientific) maintained at 228 or 30 8C [42,44,47,48]. We have also used rooms with the temperature set at 228 or 30 8C, but working at 30 o C is indeed uncomfortable for the personnel.…”

“…The key to reproducibility is accurate reporting of these seemingly mundane details, which potentially have large effects ' [87]. Although housing temperature was not included as a factor in these analyses, studies are accumulating in which experimental outcomes differ depending on the ambient temperature; these are summarized in Figure 1 [7,10,11,19,27,28,40,42,44,46,48,63,66,67,70,79,84,[88][89][90][91][92][93][94] biomedical applications, and how this condition may influence decisions for translation to the clinic (see Outstanding Questions). It is likely that many, if not all, of the metabolic abnormalities noted previously in mouse models stem largely from chronic mild cold stress and the increase in adaptive thermogenesis.…”

“…Comparisons of BAT by MRI could also prove to be a valuable and relevant biomarker of the degree of cold-stress in experimental mice at different ambient temperatures [40]. Sleep [79,94 ] Obesity [63,66,67 [7,10,12,[27][28][29]37,40,[42][43][44]46,47,63,66,67,70,71,79,84,89,93,94]). Several other conditions or phenomena that are modeled in mice and are likely to be influenced by housing temperature, but for which there is little or no published information are also listed (followed by ?).…”