Lynch Shannon E, Alsheikh Heba M, Song Patrick N, Parker Candace C, Zhang Yujun, Yates Clayton C, Larimer Benjamin M, Lapi Suzanne E, Shevde Lalita A, Sorace Anna G
Department of Radiology, The University of Alabama at Birmingham, VH G082, 1670 University Blvd, Birmingham, AL, 35233, USA.
Department of Biomedical Sciences, The University of Alabama, Birmingham, Birmingham, AL, USA.
Mol Imaging Biol. 2025 Aug 12. doi: 10.1007/s11307-025-02027-y.
Obesity and type 2 diabetes (T2D) influence the tumor microenvironment by altering glucose metabolism, which has been shown to decrease immune cell infiltration and activation. Positron emission tomography (PET) imaging provides a non-invasive method to detect molecular markers of immune populations in the tumor microenvironment and systemic organs. The goal of this study is to utilize advanced molecular imaging to quantify differences in innate and adaptive immune responses in diabetic obese mice systemically and within the tumor microenvironment.
5-6-week-old female C57BL6/J mice were placed on a high-fat diet (HFD) composed of 60% kcal fat or control low-fat diet with 10% kcal fat. Animals were treated with subsequent low doses of streptozotocin to induce T2D and blood glucose was monitored. Following induction of diabetes, E0771-luc + cells were implanted into the 4th mammary fat pad and allowed to grow to a tumor volume of 100mm. PET imaging was acquired over the course of 5 days with the following tracers: [F]-FDG PET for glucose metabolism, [Ga]Ga-RP832c (CD206) PET for M2 macrophages, and [Ga]Ga-GZP PET for granzyme B, an indicator of effector cell activation, and [F]-DPA-714 PET for neuroinflammation. Regions of interest were identified for the tumor, brain, kidneys, heart, muscle, brown adipose tissue (BAT), to characterize differences in important organs and tumor tissue. Metrics of standardized uptake value (SUV) were extracted from imaging data including mean, max, peak, and tumor-to-background ratios. Following the final imaging timepoint, tumors were extracted for biological characterization via flow cytometry.
Diabetic obese mice have no difference in tumor glucose metabolism, but have decreased FDG uptake in the brain and BAT compared to controls. Obesity and T2D systemically affect innate and adaptive immune infiltration and activation including significantly increased RP832c and GZP in muscle, heart, brain, and BAT. Hyperglycemic tumors had trending decreases in GZP SUV and increased RP832c SUV. Flow cytometry shows diabetic obese tumors have a significant increase in CD206 + macrophages and no significant difference in GZB + CD8 + T cells compared to controls.
PET imaging reveals that obesity and T2D alter glucose metabolism and immune activation while suppressing tumor-immune activation in diabetic obese mice both within the tumor microenvironment and systemically.
肥胖和2型糖尿病（T2D）通过改变葡萄糖代谢影响肿瘤微环境，已表明这会减少免疫细胞浸润和激活。正电子发射断层扫描（PET）成像提供了一种非侵入性方法，可检测肿瘤微环境和全身器官中免疫细胞群体的分子标志物。本研究的目的是利用先进的分子成像技术，量化糖尿病肥胖小鼠全身及肿瘤微环境中固有免疫和适应性免疫反应的差异。
将5-6周龄雌性C57BL6/J小鼠置于由60%千卡脂肪组成的高脂饮食（HFD）或含10%千卡脂肪的对照低脂饮食中。随后用低剂量链脲佐菌素处理动物以诱导T2D，并监测血糖。糖尿病诱导后，将E0771-luc +细胞植入第四乳腺脂肪垫，使其生长至肿瘤体积为100mm³。在5天内使用以下示踪剂进行PET成像：用于葡萄糖代谢的[¹⁸F]-FDG PET、用于M2巨噬细胞的[⁶⁸Ga]Ga-RP832c（CD206）PET、用于效应细胞激活指标颗粒酶B的[⁶⁸Ga]Ga-GZP PET以及用于神经炎症的[¹⁸F]-DPA-714 PET。确定肿瘤、脑、肾、心脏、肌肉、棕色脂肪组织（BAT）的感兴趣区域，以表征重要器官和肿瘤组织的差异。从成像数据中提取标准化摄取值（SUV）指标，包括平均值、最大值、峰值和肿瘤与背景比值。在最后一个成像时间点后，提取肿瘤进行流式细胞术生物学表征。
糖尿病肥胖小鼠的肿瘤葡萄糖代谢无差异，但与对照组相比，脑和BAT中的FDG摄取减少。肥胖和T2D全身影响固有免疫和适应性免疫浸润及激活，包括肌肉、心脏、脑和BAT中RP832c和GZP显著增加。高血糖肿瘤的GZP SUV呈下降趋势，RP832c SUV增加。流式细胞术显示，与对照组相比，糖尿病肥胖肿瘤中CD206 +巨噬细胞显著增加，GZ B + CD8 + T细胞无显著差异。
PET成像显示，肥胖和T2D在糖尿病肥胖小鼠的肿瘤微环境及全身改变葡萄糖代谢和免疫激活，同时抑制肿瘤免疫激活。
