Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature
Open accessAbstract
Significance: We show that the mandated, subthermoneutral laboratory housing temperature, which is known to cause chronic, metabolic cold stress, induces suppression of the antitumor immune response and promotes tumor growth and metastasis. When mice are housed at thermoneutrality, there are fewer immunosuppressive cells with significantly enhanced CD8 + T cell-dependent control of tumor growth. These findings underscore the fact that investigating mouse models under a single set of environmental temperature conditions may lead to a misunderstanding of the antitumor immune potential. These data also highlight the need for additional study to determine how systemic metabolic stress modulates the functions of immune effector cells, particularly in tumor-bearing mice, and whether cancer therapies, including immunotherapy, are impacted by housing temperature.
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Temperature and humidity modifies tumour progression.
“Temperature and humidity | Modifies tumour progression [186].”
From Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0 (2020) · cites this paper as [186]
The Results report slower tumor growth and fewer lung metastases in mice housed at thermoneutral rather than standard temperatures. Materials and Methods says humidity was controlled, but the paper does not report testing whether humidity modifies tumour progression. (LLM, conf=0.89)
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Cites
Brown Adipose Tissue: Function and Physiological Significance
CANNON, B., & NEDERGAARD, J. (2004) · Physiological Reviews · doi:10.1152/physrev.00015.2003 · Cited by 6,433 · see citing works
Corzo, C. A., Condamine, T., Lu, L., Cotter, M. J., Youn, J.-I., Cheng, P., Cho, H.-I., Celis, E., Quiceno, D. G., Padhya, T., et al. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100587 · Cited by 1,173 · see citing works
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Research works printed but not linked: 31
- Voskoglou-Nomikos T, Pater JL, Seymour L (2003) Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. Clin Cancer Res 9(11):4227-4239.
- Seok J, et al. (2013) Genomic responses in mouse models poorly mimic human in- flammatory diseases. Proc Natl Acad Sci USA 110(9):3507-3512.
- Lodhi IJ, Semenkovich CF (2009) Why we should put clothes on mice. Cell Metab 9(2): 111-112.
- Gaskill BN, et al. (2012) Heat or insulation: Behavioral titration of mouse preference for warmth or access to a nest. PLoS ONE 7(3):e32799.
- Karp CL (2012) Unstressing intemperate models: How cold stress undermines mouse modeling. J Exp Med 209(6):1069-1074.
- Rudaya AY, Steiner AA, Robbins JR, Dragic AS, Romanovsky AA (2005) Thermoreg- ulatory responses to lipopolysaccharide in the mouse: Dependence on the dose and ambient temperature. Am J Physiol Regul Integr Comp Physiol 289(5):R1244-R1252.
- Feldmann HM, Golozoubova V, Cannon B, Nedergaard J (2009) UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 9(2):203-209.
- Nguyen KD, et al. (2011) Alternatively activated macrophages produce catechol- amines to sustain adaptive thermogenesis. Nature 480(7375):104-108.
- Pulaski BA, Ostrand-Rosenberg S (2001) Mouse 4T1 breast tumor model. Curr Protoc Immunol May;Chapter 20:Unit 20.2.
- Danna EA, et al. (2004) Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Res 64(6): 2205-2211.
- Swann JB, et al. (2008) Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci USA 105(2): 652-656.
- Shankaran V, et al. (2001) IFNgamma and lymphocytes prevent primary tumour de- velopment and shape tumour immunogenicity. Nature 410(6832):1107-1111.
- Teng MW, et al. (2010) IL-23 suppresses innate immune response independently of IL- 17A during carcinogenesis and metastasis. Proc Natl Acad Sci USA 107(18):8328-8333.
- Huang AY, et al. (1996) The immunodominant major histocompatibility complex class I-restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product. Proc Natl Acad Sci USA 93(18):9730-9735.
- Ostrand-Rosenberg S (2008) Immune surveillance: A balance between protumor and antitumor immunity. Curr Opin Genet Dev 18(1):11-18.
- Cortez-Retamozo V, et al. (2012) Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci USA 109(7):2491-2496.
- Shimizu I, et al. (2005) Enhanced thermal avoidance in mice lacking the ATP receptor P2X3. Pain 116(1-2):96-108.
- Fox CJ, Hammerman PS, Thompson CB (2005) Fuel feeds function: Energy metabolism and the T-cell response. Nat Rev Immunol 5(11):844-852.
- Pearce EL, Pearce EJ (2013) Metabolic pathways in immune cell activation and qui- escence. Immunity 38(4):633-643.
- Martin LB, Weil ZM, Nelson RJ (2008) Seasonal changes in vertebrate immune activity: Mediation by physiological trade-offs. Philos Trans R Soc Lond B Biol Sci 363(1490): 321-339.
- Padgett DA, Glaser R (2003) How stress influences the immune response. Trends Im- munol 24(8):444-448.
- Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331(6024):1565-1570.
- Zitvogel L, et al. (2008) The anticancer immune response: Indispensable for thera- peutic success? J Clin Invest 118(6):1991-2001.
- Repasky EA, Evans SS, Dewhirst MW (2013) Temperature matters! And why it should matter to tumor immunologists. Cancer Immunol Res 1(4):1-7.
- Fisher DT, et al. (2011) IL-6 trans-signaling licenses mouse and human tumor micro- vascular gateways for trafficking of cytotoxic T cells. J Clin Invest 121(10):3846-3859.
- Hursting SD, Berger NA (2010) Energy balance, host-related factors, and cancer pro- gression. J Clin Oncol 28(26):4058-4065.
- Cannon B, Nedergaard J (2012) Yes, even human brown fat is on fire! J Clin Invest 122(2):486-489.
- Ouellet V, et al. (2012) Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest 122(2): 545-552.
- Kokolus KM, Hong CC, Repasky EA (2010) Feeling too hot or cold after breast cancer: Is it just a nuisance or a potentially important prognostic factor? Int J Hyperthermia 26(7):662-680.
- Fyfe G, et al. (1995) Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13(3):688-696.
- Lotze MT, et al. (1985) In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2. J Immunol 135(4):2865-2875.
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Binnewies, M., Roberts, E. W., Kersten, K., Chan, V., Fearon, D. F., Merad, M., Coussens, L. M., Gabrilovich, D. I., Ostrand-Rosenberg, S., Hedrick, C. C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0014-x · Cited by 6,145 · see citing works
Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0
Percie du Sert, N., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., Emerson, M., et al. (2020) · PLOS Biology · doi:10.1371/journal.pbio.3000411 · Cited by 2,677 · see citing works
Stress and cancer: mechanisms, significance and future directions
Eckerling, A., Ricon-Becker, I., Sorski, L., Sandbank, E., & Ben-Eliyahu, S. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-021-00395-5 · Cited by 348 · see citing works
Bucsek, M. J., Qiao, G., MacDonald, C. R., Giridharan, T., Evans, L., Niedzwecki, B., Liu, H., Kokolus, K. M., Eng, J. W.-L., Messmer, M. N., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0546 · Cited by 294 · see citing works
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BackgroundResultSelf-citationde Jong, J. M. A., Sun, W., Pires, N. D., Frontini, A., Balaz, M., Jespersen, N. Z., Feizi, A., Petrovic, K., Fischer, A. W., Bokhari, M. H., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0101-4 · Cited by 137 · see citing works
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Self-citationLeptin stimulates bone formation in ob/ob mice at doses having minimal impact on energy metabolism
Philbrick, K. A., Wong, C. P., Branscum, A. J., Turner, R. T., & Iwaniec, U. T. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0484 · Cited by 80 · see citing works
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- Authors
- Kokolus, K. M., Capitano, M. L., Lee, C.-T., Eng, J. W.-L., Waight, J. D., Hylander, B. L., Sexton, S., Hong, C.-C., Gordon, C. J., Abrams, S. I., & Repasky, E. A.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- Department of Immunology,
- Department of Animal Resources, and
- Environmental Protection Agency (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-11-18
- Volume
- 110
- Issue
- 50
- Pages
- 20176-20181
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3864348
- OpenAlex
- W2003173977
- Cited by
- 335
- References
- 2
- Citations by year
- 2026: 26 · 2025: 18 · 2024: 18 · 2023: 32 · 2022: 30 · 2021: 30 · 2020: 24 · 2019: 28 · 2018: 26 · 2017: 36 · 2016: 27 · 2015: 22 · 2014: 15 · 2013: 3
- FWCI
- 15.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Environmental Protection Agency
- National Cancer Institute (R01CA140622, CA016056., R01CA135368, T32CA085183, P30CA016056)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007519)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- housing temperature, thermoneutrality, cold stress, thermogenesis, antitumor immunity, tumor growth, metastasis, CD8+ T cells, tumor microenvironment, myeloid-derived suppressor cells, regulatory T cells, thermal preference, laboratory mice, ambient temperature
- MeSH terms
- Analysis of Variance, Animals, Blood Cell Count, Female, Housing, Animal, Immunohistochemistry, Immunotherapy, Mice, Inbred BALB C, Neoplasms, Stress, Physiological, Temperature, Linear Models, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Mice
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