Innate Immune Mechanisms Contributing to Cancer Growth in Obesity

补充项目摘要 肥胖(身体质量指数≥30公斤/平方米)影响着至少三分之一的美国人口，更普遍 在非裔美国人和西班牙裔人口中，并增加了发展和死亡的风险 某些癌症。然而，这些风险背后的细胞和分子机制尚不清楚。我们的 研究表明，在饮食诱导下，结直肠癌和其他肿瘤生长得相当快。 肥胖小鼠由于酸敏感受体G蛋白偶联65(GPR65)的免疫抑制作用， 肿瘤相关巨噬细胞(TAMs)。在父项目中，我们正在分析来自 改变功能和肥胖小鼠肿瘤生长的GPR65，确定了高脂 饮食(HFD)促进TAM中GPR65信号转导，并评估靶向GPR65治疗肿瘤的效果 肥胖和非肥胖小鼠的免疫治疗。来自父项目的数据表明，脂类代谢改变 负责上调肥胖小鼠肿瘤TAMs上GPR65的表达。因为他的血脂水平 肥胖人类的肿瘤与肥胖小鼠的肿瘤几乎相同，我们相信有很高的 来自肥胖人类的肿瘤可能会表现出类似的免疫特征。在拟议的补编中 项目，我们将把我们的研究扩展到人类癌症，包括结直肠癌、肝细胞癌、胰腺癌 腺癌(PDAC)和乳腺癌，以检验TAM上GPR65表达的假设 与肥胖、功能改变和肿瘤中其他免疫细胞的改变有关 微环境。我们进一步假设，肥胖对癌症免疫细胞的影响是相同的。 在非裔美国人、西班牙裔、亚裔和非西班牙裔白人群体中，并不是根据 种族或民族。为了分析肿瘤，我们将使用质量细胞术(CyTOF)来检测频率， 肿瘤中免疫细胞的表面和细胞因子谱，使用单细胞RNA测序(ScRNA Seq)来 分析这些细胞的功能轮廓，并使用CODEX分析TAM之间的空间关系 和其他免疫细胞。然后我们将比较来自不同种族和不同种族患者的肿瘤结果 种族背景。这些实验的结果有望证实我们的假设和 为未来的研究提供了强有力的理论基础，在这些研究中，这些假设将在更大的人群中进行测试，并且 针对GPR65的治疗方法被开发出来，并在临床试验中进行评估。

Supplement Project Summary Obesity (body mass index ≥30 kg/m2), which affects at least one-third of the U.S. population, is more prevalent among African American and Hispanic populations and increases the risks of both developing and dying from certain cancers. However, the cellular and molecular mechanisms underlying these risks are unknown. Our studies demonstrate that colorectal cancer (CRC) and other tumors grow considerably faster in diet-induced obese mice due to the immunosuppressive actions of the acid-sensing receptor, G-protein coupled 65 (GPR65), on tumor-associated macrophages (TAMs). In the parent project, we are analyzing the intracellular signals from GPR65 that alter TAM function and tumor growth in obese mice, identifying the mechanism by which a high-fat diet (HFD) promotes GPR65 signaling in TAMs, and assessing the effects of targeting GPR65 for tumor immunotherapy in obese and non-obese mice. Data from the parent project indicate that altered lipid metabolism is responsible for upregulating GPR65 expression on TAMs in the tumors of obese mice. Since the lipid profile in tumors of obese humans is nearly identical to that of tumors from obese mice, we believe there is a high likelihood that tumors from obese humans will display a similar immune profile. In the proposed supplement project, we will extend our studies to human cancers including CRC, hepatocellular carcinoma (HCC), pancreatic adenocarcinoma (PDAC) and breast carcinomas in order to test the hypothesis that GPR65 expression on TAMs is associated with obesity, altered TAM function and alterations of other immune cells in the tumor microenvironment. We further hypothesize that these effects of obesity on immune cells in cancer are equivalent in African American, Hispanic, Asian and non-Hispanic White populations and not determined on the basis of race or ethnicity. To analyze the tumors, we will use mass cytometry (CyTOF) to examine the frequencies, surface, and cytokine profiles of immune cells in the tumor, use single cell RNA sequencing (scRNA seq) to analyze the functional profiles of these cells and use CODEX to analyze the spatial relationships between TAMs and other immune cells. We will then compare the results between tumors from patients of different racial and ethnic backgrounds. The results of these experiments are expected to confirm both of our hypotheses and provide a strong rationale for future studies in which these hypotheses are tested in larger populations, and novel therapies targeting GPR65 are developed and evaluated in clinical trials.