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Housing temperature-induced stress drives therapeutic resistance in murine tumour models through ?2-adrenergic receptor activation.

ABSTRACT: Cancer research relies heavily on murine models for evaluating the anti-tumour efficacy of therapies. Here we show that the sensitivity of several pancreatic tumour models to cytotoxic therapies is significantly increased when mice are housed at a thermoneutral ambient temperature of 30?°C compared with the standard temperature of 22?°C. Further, we find that baseline levels of norepinephrine as well as the levels of several anti-apoptotic molecules are elevated in tumours from mice housed at 22?°C. The sensitivity of tumours to cytotoxic therapies is also enhanced by administering a ?-adrenergic receptor antagonist to mice housed at 22?°C. These data demonstrate that standard housing causes a degree of cold stress sufficient to impact the signalling pathways related to tumour-cell survival and affect the outcome of pre-clinical experiments. Furthermore, these data highlight the significant role of host physiological factors in regulating the sensitivity of tumours to therapy.

SUBMITTER: Eng JW

PROVIDER: S-EPMC4471870 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation.

Eng Jason W-L JW Reed Chelsey B CB Kokolus Kathleen M KM Pitoniak Rosemarie R Utley Adam A Bucsek Mark J MJ Ma Wen Wee WW Repasky Elizabeth A EA Hylander Bonnie L BL

Nature communications 20150310

Cancer research relies heavily on murine models for evaluating the anti-tumour efficacy of therapies. Here we show that the sensitivity of several pancreatic tumour models to cytotoxic therapies is significantly increased when mice are housed at a thermoneutral ambient temperature of 30 °C compared with the standard temperature of 22 °C. Further, we find that baseline levels of norepinephrine as well as the levels of several anti-apoptotic molecules are elevated in tumours from mice housed at 22 ...[more]

PMID: 25756236

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Project description:BackgroundAlthough programmed cell death protein 1 (PD-1) inhibitors have revolutionised treatment for advanced melanoma, not all patients respond. We previously showed that inhibition of the flavoprotein renalase (RNLS) in preclinical melanoma models decreases tumour growth. We hypothesised that RNLS inhibition promotes tumour rejection by effects on the tumour microenvironment (TME).MethodsWe used two distinct murine melanoma models, studied in RNLS knockout (KO) or wild-type (WT) mice. WT mice were treated with the anti-RNLS antibody, m28, with or without anti-PD-1. 10X single-cell RNA-sequencing was used to identify transcriptional differences between treatment groups, and tumour cell content was interrogated by flow cytometry. Samples from patients treated with immunotherapy were examined for RNLS expression by quantitative immunofluorescence.ResultsRNLS KO mice injected with wild-type melanoma cells reject their tumours, supporting the importance of RNLS in cells in the TME. This effect was blunted by anti-cluster of differentiation 3. However, MØ-specific RNLS ablation was insufficient to abrogate tumour formation. Anti-RNLS antibody treatment of melanoma-bearing mice resulted in enhanced T cell infiltration and activation and resulted in immune memory on rechallenging mice with injection of melanoma cells. At the single-cell level, treatment with anti-RNLS antibodies resulted in increased tumour density of MØ, neutrophils and lymphocytes and increased expression of IFNγ and granzyme B in natural killer cells and T cells. Intratumoural Forkhead Box P3 + CD4 cells were decreased. In two distinct murine melanoma models, we showed that melanoma-bearing mice treated with anti-RNLS antibodies plus anti-PD-1 had superior tumour shrinkage and survival than with either treatment alone. Importantly, in pretreatment samples from patients treated with PD-1 inhibitors, high RNLS expression was associated with decreased survival (log-rank P = 0.006), independent of other prognostic variables.ConclusionsRNLS KO results in melanoma tumour regression in a T-cell-dependent fashion. Anti-RNLS antibodies enhance anti-PD-1 activity in two distinct aggressive murine melanoma models resistant to PD-1 inhibitors, supporting the development of anti-RNLS antibodies with PD-1 inhibitors as a novel approach for melanomas poorly responsive to anti-PD-1.

Dataset Information

Housing temperature-induced stress drives therapeutic resistance in murine tumour models through ?2-adrenergic receptor activation.

Publications

Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation.

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