Translational Imaging Markers for Metabolic Potentiation of Immunotherapy

Immune checkpoint inhibitor (ICI) has become an important treatment modality for triple- negative breast cancer (TNBC). However, TNBC tumors have relatively low mutation burden and neoantigen counts but are enriched with myeloid derived suppressor cells (MDSC) and M2-like tumor associated macrophages, both shaping an immune suppressive tumor microenvironment. Leveraging on its ability to release neoantigen, chemotherapy is combined with ICI in the clinic to enhance the efficacy of ICI therapy, however the response rate to ICI+chemotherapy is modest. Therefore, developing an effective strategy to enhance anti-tumor efficacy of ICI will address this unmet clinical need. Analysis of The Cancer Genome Atlas (TCGA) suggest that TNBC's glutamine metabolic signature is associated with low anti-tumor immune signature and unfavorable prognosis of TNBC patients. Our preliminary studies have tested two FDA-approved investigational new drugs (IND) and shown that targeting glutamine metabolism overcame the resistance to ICI in TNBC models and glutamine antagonism enhanced the efficacy of ICI+chemotherapy to inhibit tumor growth. In this application, we will validate the strategy of targeting glutamine metabolic signature in the setting of ICI therapy and assess the ability of [18F](2S,4R)4-Fluoroglutamine (4F-Gln) and [18F]FDG PET to detect glutamine antagonism and immune activation, respectively and to predict survival (Aim- 1). We will elucidate cancer versus immune cell contribution to 4F-Gln and FDG PET signal, particularly, we aim to determine the extent to which overall FDG PET uptake at baseline and post-treatment is driven by immune cells versus cancer cells in the tumor, and whether increased FDG uptake post-therapy is associated with immune activation by comparing FDG uptake in immune cells with the expression of immune activation markers including CD69 (Aim-2). To facilitate the clinical translation of precision imaging markers, we will validate [18F]Fluciclovine for detecting glutamine antagonism and implement a dual tracer (Fluciclovine/FDG) protocol in single PET session (Aim-3). Given that TNBC is highly heterogeneous in glutamine metabolic machinery as well as responses to ICI, the highly translational treatment approach and precision imaging markers validated in this application can lead to a window of opportunity trial upon successful completion of this project. . Project Number: 1R01CA301356-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Rong Zhou (+1 co-PI) | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $674,339 | Activity Code: R01 | Study Section: Imaging Probes and Contrast Agents Study Section[IPCA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11306336