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Exploiting the thermal regulation of T cell activation to invigorate the immune response to breast cancer
C. SCIENTIFIC ABSTRACT Scientific Abstract Background: Vaccines for breast cancer have so far been disappointing in terms of their ability to prevent or even slow down disease progression in women with breast cancer even though considerable excitement surrounded many of these treatments during their pre-clinical evaluation in mouse models. One reason for this may be that in humans, the T lymphocyte response is defective or tolerized in comparison to those in mouse models. A major problem that, if solved, could enable many vaccines to work more effectively is the lack of effective ¡§adjuvants¡¨ for human use, the substances that are added along with vaccines to help stimulate sluggish immune cells. The mentor¡¦s laboratory has obtained descriptive evidence that mild, whole body fever-like thermal stress could serve to provide a highly specific activating signal to the immune system. However, the molecular and cellular mechanism by which the thermal stress influences host T cell dependent immune responses to tumor antigen is not clear. Hypothesis: The activation threshold of T lymphocytes is lowered, and the cellular immune response to breast cancer associated antigen is improved, by fever-like thermal stress. Provocative preliminary data supports this hypothesis. Specific Aims: In Specific Aim 1, we will test the hypothesis that thermal stress regulates the function of molecules that are involved in the regulation of the T cell activation threshold. In Specific Aim 2, we will test the hypothesis that exposure of primary T cells to mild thermal stress is able to enhance their anti-tumor activity using neu-transgenic mice as a clinically relevant, murine breast cancer model. Study Design: We will first define the molecular components of the signaling pathways engaged by the human TCR in the context of normothermic (37?aC) and hyperthermic (39.5?aC) conditions. We will also challenge the ¡§pre-heated¡¨ primary T cells of neu-transgenic mice using neu antigen presented by APC and compare its IL-2 production with the non-¡§pre-heated¡¨ neu-challenged T cells. We will determine whether T cells of neu-transgenic mice could prevent tumor cell growth in vitro following mild hyperthermic stress and evaluate breast tumor control in vivo after the neu-transgenic mice are exposed to fever-range whole body hyperthermia. Potential Outcomes and Benefits of the Research: Several exciting immunotherapy strategies have already been developed for breast cancer and have shown efficacy in animal models. However, these same strategies have been disappointing when extended to patients with breast cancer. This research could provide support for the addition of fever-like thermal stress as a feasible and safe adjuvant to these protocols and thus could result in a rapid improvement in survival and a decrease in the death from this disease.
General Audience Summary (Lay Abstract) Over several decades, the scientific community has tested various molecules, especially ones isolated from bacteria, for their ability to serve as ¡§adjuvants¡¨ or substances that can help to stimulate a more effective immune response to cancer vaccines. One of the major reasons that the most effective adjuvant known (complete Freund¡¦s adjuvant) cannot be used in cancer patients is that it is considered too toxic for human use, in part due to its known induction of high fevers. The candidate read about the research taking place in the Mentor¡¦s laboratory at Roswell Park Cancer Institute, specifically the question of whether an increase in body temperature associated with fever could be helpful in controlling the growth of tumors in animal models and in patients, and she became committed to pursuing a training opportunity that would utilize her previous training in molecular biology and immunology to address new hypotheses relating to hyperthermia, T lymphocyte activation and cancer therapy. Specifically, the candidate has become extremely interested in pursuing the novel idea that taking advantage of the febrile response, as an adjuvant, can help to stimulate a more effective immune response. The candidate has previous experience in the molecular biology of activation and has developed expertise in the study of signaling pathways thus this postdoctoral opportunity represents an outstanding opportunity for her to apply her previous training toward solving a problem that has greatly slowed the prevention of death from breast cancer: the inability of the T lymphocytes in cancer patients to function more quickly and completely. In this study, the candidate will test the hypothesis that T lymphocytes, which are critical components of the body¡¦s natural defense against tumors, are sensitive to body temperature and can function more effectively after being warmed to fever range temperatures. In Specific Aim 1, she will first define more completely the molecular components of the signaling pathways engaged by these cells in the context of normothermic (37?aC) and hyperthermic (39.5?aC) condition. In Specific Aim 2, she will investigate whether exposure of primary T cells to mild thermal stress is able to enhance its anti-tumor activity in a clinically relevant model of human breast cancer, the neu-transgenic mouse. Since there has been recent recognition that the addition of hyperthermia to radiation treatments can extend survival of cancer patients, including breast cancer patients, this postdoctoral research could contribute to the rationale for the increased use of fever-range hyperthermia in clinical trials, especially those patients who may be receiving immunotherapy. As a result, this research could have a rapid impact on the improved survival of patients after breast cancer.