Thermoneutrality, Mice, and Cancer: A Heated Opinion

Hylander, Bonnie L.; Repasky, Elizabeth A.

doi:10.1016/j.trecan.2016.03.005

Cited by 85 publications

(83 citation statements)

References 90 publications

(179 reference statements)

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“…These findings have broad implications related to the baseline immunosuppression of tumor-bearing mice housed at 22°C (15,16,32) and could help to explain why the remarkable responses seen in some patients receiving a single checkpoint inhibitor in a therapeutic setting are generally not observed in mice (33,34). …”

Section: Discussionmentioning

confidence: 90%

β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

et al. 2017

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The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies - physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-adrenergic receptor knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intra-tumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of PD-1, in addition to an elevated effector CD8+ T cell to CD4+ regulatory T cell ratio (IFN-γ+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-adrenergic receptor signaling to regulate the immune status of the tumor microenvironment and supports the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy.

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Section: Discussionmentioning

confidence: 90%

β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

et al. 2017

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“…Housing temperature, especially cold exposure, impacts on metabolic homeostasis as illustrated by the effects it has on BAT and ‘browning’. However, much less is known on the effects of ‘browning’ interventions in animals maintained at thermoneutrality [2, 17]. Our major finding is that chronic exposure to a mild-cold stimulus (i.e.…”

Section: Discussionmentioning

confidence: 99%

Cold exposure drives weight gain and adiposity following chronic suppression of brown adipose tissue

Aldiss

Lewis

Lupini

et al. 2019

Preprint

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Background and aim:Rodents are commonly housed below thermoneutrality and this exposure to 'cold' (i.e. 20°C) activates thermogenic brown (BAT) and beiging of white adipose tissue. Here, we examined whether a standard housing temperature (i.e. 20°C, a reduction in temperature of ~8°C) or YM-178, a highly-selective β 3-adrenoreceptor agonist, in obese animals raised at thermoneutrality, would impact differently on classical BAT or subcutaneous inguinal (IWAT) beige depots. Methods: Eighteen weanling Sprague-Dawley rats were housed at thermoneutrality (28°C) and fed a high-fat diet. At 12 weeks, 6 animals were randomised to either standard housing temperature (20°C, n=6) or to β 3-AR agonist administration (28°C+β3, 0.75mg/kg/d, n=6) for 4 weeks. Metabolic assessment was undertaken during the final 48h, followed by interscapular, perivascular BAT and IWAT sampling for the analysis of thermogenic genes and the proteome. Results: Exposure to 20°C increased weight gain, BAT and IWAT mass. Proteomic analysis of BAT revealed novel pathways associated with cold-induced weight gain (i.e. histone deacetylation, glycosaminoglycan degradation and glycosphingolipid biosynthesis) whilst β 3adrenoreceptor agonism impacted on proteins involved in skeletal muscle contraction and cell differentiation. IWAT of cold-exposed animals exhibited an enrichment of proteins involved NAD+ binding, plus retinol and tyrosine metabolic pathways whilst β 3-AR agonism downregulated ribosomal and upregulated acute phase response proteins. Conclusion: Following diet-induced obesity at thermoneutrality, exposure to 20°C promotes subcutaneous fat deposition in order to reduce heat loss and defend body temperature. In contrast, chronic administration of β 3-AR agonist has minimal metabolic-related effects on adipose tissue.

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“…[331][332][333][334][335][336] Temperature and humidity Thermoneutral housing temperature (26°-34°C): reduced tumor formation, growth rate and metastasis due to increased CD8+ T cells; reduced myeloid-derived suppressor cells and Tregs. 327,328,[337][338][339][340][341][473][474][475][476] Sub-thermoneutral housing temperature (20°-26°C): suppressed immune responses; increased therapeutic resistance of tumor and GVHD severity; suppressed myeloid cells function; alternative activation of macrophages. Elevated humidity: increased bioburden; high ammonia levels due to expansion in urea-converting microflora.…”

Section: Environmental Enrichmentmentioning

confidence: 99%

“…Higher humidity is associated with increased levels of ammonia and bioburden with severe impairment of respiratory mucosal immune response and increased risk of opportunistic infections, respectively. 327,328,[337][338][339][340][341][342] Illumination (Light) Circadian and light effects on immunity are recognized in many species, including humans and mice. Albino animals have higher light sensitivity, and a number of common mouse strains are blind with retinal degeneration but still exhibit responses to light and light cycles.…”

Section: Crispr-cas9mentioning

confidence: 99%

Immune Relevant and Immune Deficient Mice: Options and Opportunities in Translational Research

Radælli

Santagostino²,

Sellers

et al. 2018

ILAR Journal

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In 1989 ILAR published a list and description of immunodeficient rodents used in research. Since then, advances in understanding of molecular mechanisms; recognition of genetic, epigenetic microbial, and other influences on immunity; and capabilities in manipulating genomes and microbiomes have increased options and opportunities for selecting mice and designing studies to answer important mechanistic and therapeutic questions. Despite numerous scientific breakthroughs that have benefitted from research in mice, there is debate about the relevance and predictive or translational value of research in mice. Reproducibility of results obtained from mice and other research models also is a well-publicized concern. This review summarizes resources to inform the selection and use of immune relevant mouse strains and stocks, aiming to improve the utility, validity, and reproducibility of research in mice. Immune sufficient genetic variations, immune relevant spontaneous mutations, immunodeficient and autoimmune phenotypes, and selected induced conditions are emphasized.

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Thermoneutrality, Mice, and Cancer: A Heated Opinion

Cited by 85 publications

References 90 publications

β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

Cold exposure drives weight gain and adiposity following chronic suppression of brown adipose tissue

Immune Relevant and Immune Deficient Mice: Options and Opportunities in Translational Research

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