Sunday, December 22, 2024
12/22/2024
Project Abstract/Summary For decades, animals in biomedical research have yielded significant scientific and medical breakthroughs by generating the essential preclinical data that ultimately support the discovery and development of treatments for human diseases, including cancer. However, while we to rely on animal models to investigate the complexity of cancer and cancer therapies, these preclinical studies have alarmingly low success in reproducibility, and even lower preclinical-to-clinical success rates. As per the Guide for the Care and Use of Laboratory Animals 8th Edition, research institutions have standardized, minimum guidelines for the housing, husbandry, and overall care for laboratory animals that they must adhere to. A mildly cool ambient temperature is a critical aspect of animal housing that has been shown to elicit significant physiological changes to research rodents, driven by the activation of the sympathetic nervous system and increased β- adrenergic receptor (β-AR) signaling as a result of the systemic release of norepinephrine. This is due to the compensatory response, known as non-shivering thermogenesis, employed by rodents housed at temperatures that fall below their thermoneutral zone (which is the range of ambient temperatures at which heat generated by basal metabolism is sufficient for maintaining homeostatic core temperature. ) Our lab has previously established that standard (ST), subthermoneutral laboratory housing temperatures result in significant impairment to the murine CD8+ T cell-dependent anti-tumor immune response compared to mice house at thermoneutral temperatures (TT). Additionally, we have shown that the immune checkpoint inhibitor αPD-1, an immunotherapy that has recently seen success as a front-line approach to treating cancers like melanoma, has improved efficacy in treating tumor-bearing mice housed at TT in a β-AR-dependent manor. Although published and preliminary data indicate a role for the co-receptor, CD28, in the diminished anti-tumor function of CD8+ T cells as a result of increased β-AR signaling, a gap exists in our understanding of the mechanisms underlying the reduced CD8+ T cell activation and effector function in mice housed at ST. Therefore, we propose using genetically engineered mouse models to precisely interrogate CD28 signaling and test hypothesis that standard housing temperatures impairs CD8+ T cell anti-tumor immunity and the in vivo efficacy of αPD-1 via impaired CD28 co-stimulation. We will use in vitro and in vivo approaches to examine the effects of housing temperature on CD8+ T cell CD28 expression and signaling, as well as tumor- infiltrating lymphocytes in mice treated with αPD-1 therapy. The studies outline in this proposal have the potential to identify a previously undefined mechanism by which subthermoneutral laboratory animal housing temperatures influence experimental outcomes of cancer and immunotherapy models, while also characterizing a widely underappreciated variable that exists in our animal models.
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