The effects of obesity on cancer treatment efficacy remain unclear, as both beneficial and detrimental modulations of the tumor immune microenvironment have been reported. We compared 68Ga-NOTA-GZP (βAla–Gly–Gly–Ile–Glu–Phe–Asp–CHO) PET images with those obtained with the gold standard, 18F-FDG PET, to quantify biologic variations in a diet-induced obesity model of triple-negative breast cancer to understand how obesity influences the tumor immune landscape and response to immunotherapy. Methods: C57BL6/J mice were fed a high-fat diet (n = 24) or low-fat diet (n = 18) for 14 wk. EO771 tumor-bearing mice were treated with a fixed or weight-based dose of saline or checkpoint-blockade immunotherapy, and tumor volume was evaluated for long-term response. Mice were imaged via 68Ga-NOTA-GZP PET on day 7 to quantify immune activation, and those images were compared with 18F-FDG PET images to characterize changes in glucose metabolism on days 0 and 6. SUV was quantified from imaging data, and a cohort of mice was euthanized to validate biologic changes via flow cytometry. Results: Mice fed a high-fat diet demonstrated increased tumor glucose metabolism at baseline, as measured by 18F-FDG PET. No significant differences were observed in 18F-FDG SUV for responder tumors on day 6. The 68Ga-NOTA-GZP PET signal was increased in tumors responsive to immunotherapy on day 7 and was highly sensitive in predicting response via analysis of receiver-operating-characteristic curves. Conclusion: Obesity decreases response to immunotherapy by altering metabolism and the tumor immune microenvironment. 68Ga-NOTA-GZP PET imaging is a sensitive and predictive imaging biomarker of immunotherapy response, but weight-based dosing is needed to achieve effective changes in tumor volume.
