Immunomodulation by dietary protein restriction

项目总结 免疫疗法，特别是免疫检查点抑制剂，正在彻底改变治疗模式。 治疗几个实体肿瘤。然而，到目前为止，对去势抵抗的患者对这些药物的反应 前列腺癌(CRPC)的发病率一直不高，尽管一种名为siPuleucel-T的疫苗疗法已经获得批准 基于生存数据。已经提出了几个假说来解释这种内在的抗性，包括 免疫抑制的前列腺癌微环境。据报道，改变饮食会对 肿瘤发生和肿瘤进展，包括前列腺癌模型。限制蛋氨酸的饮食有 已被证明可以延长啮齿动物的寿命，减少健康动物的炎症，并增强 代谢活动。含硫氨基酸，如蛋氨酸和胱氨酸，是硫醇和 对包括免疫系统在内的几个细胞过程至关重要。我们实验室的结果表明，饮食 蛋白质限制显著降低抗去势前列腺癌临床前模型中的肿瘤生长 癌症。抑制肿瘤生长与M2减少肿瘤浸润性巨噬细胞有关。 免疫抑制表型。我们的初步数据还表明，蛋氨酸限制在体外诱导 骨髓来源的巨噬细胞向M1免疫促进表型的极化。因此，有一个 确定饮食蛋白质修饰的作用，特别是蛋氨酸限制对 调节前列腺癌患者的免疫反应。 我们的中心假设是，饮食中蛋白质摄入量的减少可能会对前列腺产生重大影响 改善免疫抑制微环境和增强天然免疫和获得性免疫的癌症 回应。这项建议的主要目标是利用饮食干预在治疗糖尿病中的作用。 前列腺癌在免疫治疗方面的设置。 具体目标：为了实现我们的目标，我们将追求以下具体目标：1)评估 限制饮食蛋白质或蛋氨酸在体内外对前列腺癌微环境的影响；2) 确定蛋白质饮食改变或限制蛋氨酸对前列腺癌疗效的影响 免疫疗法 这项拟议的研究具有很高的创新性，它引入了饮食调整作为一种辅助治疗方法。 前列腺癌。我们提议的研究将确定改变氨基酸饮食如何增强反应。 进行免疫治疗。这将通过促进饮食和营养知识的发展为科学领域做出贡献。 CAP/癌症，重点是推进免疫治疗。本研究的译本 可能为CAP患者提供新的、侵入性更小、更有吸引力的辅助治疗。

PROJECT SUMMARY Immunotherapies, and specifically immune-checkpoint inhibitors, are revolutionizing the therapeutic paradigm for several solid tumors. To date, however, the response to these drugs in patients with castration resistance prostate cancer (CRPC) has been modest, despite that a vaccine therapy, sipuleucel-T, has been approved based on survival data. Several hypotheses have been proposed to explain this intrinsic resistance, including an immunosuppressive prostate tumor microenvironment. Diet modifications have been reported to impact tumorigenesis and tumor progression, including prostate cancer models. Dietary restriction of methionine has been shown to extend the lifespan of rodents, to reduce inflammation in healthy animals and to enhance metabolic activity. Sulfur containing amino acids such as methionine and cystine are precursors for thiols and critical for several cellular processes including immune system. Results from our lab have shown that dietary protein restriction significantly decreases tumor growth in preclinical models of castration resistant prostate cancer. The inhibition of tumor growth is associated with reduction of tumor infiltrating macrophages with M2, immunosuppressive phenotype. Our preliminary data also show that methionine restriction induces in vitro polarization of bone marrow-derived macrophages to a M1, immunopromoting phenotype. Thus, there is a rationale to determine the role of dietary protein modification and, in particular methionine restriction, on modulating the immune response in prostate cancer. Our central hypothesis is that reduction in dietary protein intake may have a significant impact on prostate cancer by modifying the immunosuppressive microenvironment and enhancing innate and adaptive immune response. The principal objective of this proposal is to exploit the role of diet intervention in the treatment of prostate cancer in the setting of immunotherapies. Specific Aims: To achieve our goal we will pursue the following specific aims: 1) To assess the impact of dietary protein or methionine restriction on the prostate tumor microenvironment both in vitro and in vivo; 2) To determine the impact of protein diet modification or methionine restriction on prostate tumor response to immunotherapies The proposed study is highly innovative by introducing diet modifications as an adjuvant treatment in in prostate cancer. Our proposed studies will determine how altered amino acid diets may enhance the response to immunotherapeutic treatments. This will contribute to the scientific field by advancing knowledge of diet and CaP/cancer in general with a focus of advancing immunotherapeutic treatments. Translation of this research may provide novel less invasive and more appealing adjuvant treatments for CaP patients.