Abstract 4154: PET imaging to characterize the tumor microenvironment in a breast cancer model of obesity
Authors: Lynch Shannon E. , Crawford Corinne , Hunt Addison , Sligh Luke , Larimer Benjamin M. , Lapi Suzanne E. , Sorace Anna G. 
Published: March 2024

Introduction: Obesity is known to reduce efficacy for cancer treatment patients and is thought to modulate the tumor microenvironment and glucose metabolism. In this study, we aim to quantify obesity-induced differences in the breast cancer tumor microenvironment with positron emission tomography (PET) imaging of hypoxia, glucose metabolism, and granzyme B. These experiments are testing the hypothesis that tumors in obese mice have increased glucose metabolism and hypoxia, measured by [18F]F-fluorodeoxyglucose (FDG) and [18F]F-fluoromisonidazole (FMISO) uptake. We also hypothesize that immunotherapy (IMT) increases immune activation, as measured by [68Ga]Ga-Granzyme B peptide (GZP), and that obese mice will respond less to immunotherapy than lean mice.

Methods: C57/Bl6 mice were placed on a high-fat diet (HFD) with 60% kcal fat (n=18) or low-fat diet (LFD) composed of 10% kcal fat (n=18) to induce obesity. Blood serum was collected for analysis of cholesterol levels prior to tumor implantation. Body weight and food intake were measured weekly. 14 weeks after initiating each diet, 5x105 E0771 cells were implanted into the 3rd mammary fat pad and allowed to grow to 50-150mm3. Tumor-bearing mice were imaged with [18F]F-FDG and [18F]F-FMISO PET to measure glucose metabolism and hypoxia, respectively prior to treatment. Following imaging, mice began treatment with either saline (n=6/diet) or checkpoint blockade IMT with 200 ug anti-PD-1 and 100 ug anti-CTLA-4 (n=12/diet). After 3 doses of IMT, mice were imaged with [68Ga]Ga-GZP PET to measure immune activation. Tumor volume measurements and treatment administration occurred every 3 days. Metrics of standardized uptake value (SUV) including mean, max, and peak were quantified from imaging data. A one-way independent ANOVA or independent t-test was used to compare differences between groups.

Results: HFD-fed mice had significantly increased body weight (p&lt;0.0001) and serum cholesterol (p=0.005) compared to LFD-fed mice. SUVmean for tumor hypoxia (p=0.003) and glucose metabolism (p=0.02) were significantly increased at baseline in HFD-fed mice compared to LFD-fed mice. IMT increases immune activation for both LFD-fed (p=0.009) and HFD-fed mice (p=0.05). IMT treatment significantly reduces tumor burden for LFD mice (p&lt;0.0001), but not HFD mice (p=0.096).

Conclusions: Obesity plays a role in the reduction of the effectiveness of immunotherapy. At baseline, tumors of obese mice have increased tumor glucose metabolism and hypoxia. Although immunotherapy increases immune activation, this is not sufficient to reduce tumor burden or improve overall survival. Understanding obesity-induced differences in tumor biology may provide imaging-directed treatment decision making.

Citation Format: Shannon E. Lynch, Corinne Crawford, Addison Hunt, Luke Sligh, Benjamin M. Larimer, Suzanne E. Lapi, Anna G. Sorace. PET imaging to characterize the tumor microenvironment in a breast cancer model of obesity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4154.