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Dysregulated metabolism is one of the key characteristics of cancer cells. The most prominent alterations are present during regulation of cell respiration, which leads to a switch from oxidative phosphorylation to aerobic glycolysis. This metabolic shift results in activation of numerous signaling and metabolic pathways supporting cell proliferation and survival. Recent progress in genetics and metabolomics has allowed us to take a closer look at the metabolic changes present in pheochromocytomas (PHEO) and paragangliomas (PGL). These neuroendocrine tumors often exhibit dysregulation of mitochondrial metabolism, which is driven by mutations in genes encoding Krebs cycle enzymes or by activation of hypoxia signaling. Present metabolic changes are involved in processes associated with tumorigenesis, invasiveness, metastasis, and resistance to various cancer therapies. In this review, we discuss the metabolic nature of PHEOs/PGLs and how unveiling the metabolic disturbances present in tumors could lead to identification of new biomarkers and personalized cancer therapies. Clin Cancer Res; 22(20); 5001–11. ©2016 AACR.See all articles in this CCR Focus section, “Endocrine Cancers: Revising Paradigms.”

Background and Purpose: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine/neural crest cell tumors. Therapeutic options for PHEOs/PGLs are limited, particularly in metastatic patients. Therefore, efforts to find new and more effective therapies are crucial in PHEO/PGL research. Recently, immunotherapy based on activation of innate immunity via pathogen-associated molecular patterns (PAMPs) has been tested in melanoma. PAMPs-based immunotherapy uses mannan, a simple polysaccharide from Saccharomyces cerevisiae, as a ligand stimulating phagocytosis in combination with toll-like receptor (TLR) ligands. Thus, in the present study we evaluated (1) the effect of intratumorally administered mannan-BAM + TLR ligands in a PHEO mouse model, (2) the participation of innate immunity on the PHEO growth reduction, (3) the leukocyte infiltration in treated PHEO, and (4) in vitro interactions of PHEO cells (with or without mannan) with neutrophils. Methods: PHEO cells were subcutaneously transplanted into mice and mannan-BAM + TLR ligands were intratumorally administered. CD45+ infiltration in tumors was measured using flow cytometry. In vitro experiments were performed using mouse/human PHEO cell lines incubated with mouse/human neutrophils. Results: The intratumoral administration of mannan-BAM and TLR ligands into PHEO resulted in 90% tumor growth reduction. The survival median increased from 16 days in the control group to 50 days in the group treated with mannan-BAM + TLR ligands. Subsequently, mice lacking functional T and B cells were used. Intratumoral administration of mannan-BAM + TLR ligands resulted in 86% reduction of tumor growth, which proved the key role of innate immunity in PHEO tumor elimination. The flow cytometry analysis of tumor-infiltrating CD45+ cells revealed higher levels of CD45+ cells in the group treated by mannan-BAM + TLR ligands. Significant increase in the levels of granulocytes was observed on days 3 and 18 of the treatment. Cytotoxic experiments using PHEO cell lines revealed increased cytotoxic effect of neutrophils toward PHEO cells labeled with mannan-BAM compared to the cells without mannan-BAM. Microscopic evaluation of neutrophils and PHEO cells labeled with mannan-BAM revealed enhanced frustrated phagocytosis and neutrophils rosette formation dependent on the presence of mannan-BAM. Conclusion: We demonstrate excellent therapeutic effects of enhanced innate immunity using intratumorally administered PAMPs and TLR ligands in a subcutaneous PHEO mouse model. Citation Format: Veronika Caisova, Garima Gupta, Ivana Jochmanova, Abhishek Jha, Liping Li, Thanh Truc Huynh, Ying Pang, Hans Kumar Ghayee, David Taïeb, Jan Zenka, Karel Pacak. Improved mice survival by reducing pheochromocytoma burden through activation of innate immunity using mannan and toll-like receptors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B90.