Bitter taste receptors in oral cancer tumor-associated macrophages

Oral squamous cell carcinomas (OSCCs) are associated with poor prognosis and a 5-year mortality rate of approximately 50%. These tumors are influenced by the cancer cells, tumor microenvironment, and host immune system, with tumor-associated macrophages (TAMs) playing a pivotal role in shaping the immune response and clinical outcomes. Macrophages exhibit diverse activation states, broadly categorized into pro- inflammatory (M1) and anti-inflammatory (M2) subtypes, impacting tumor progression and metastasis. Targeting macrophage pathways has emerged as a promising therapeutic approach for solid tumors, including OSCC, but the underlying signaling pathways that mediate cancer and immune cell interactions are poorly understood. Our group previously identified bitter taste G protein-coupled receptors (T2Rs) as important sentinels of immunity on immune cells such as macrophages where they enhance bacterial phagocytosis. We also found that T2Rs are expressed on OSCC cells, where activation leads to apoptosis; furthermore, expression of some T2Rs (including T2R4 and 14 genes/proteins) is associated with OSCC patient survival. We postulate that T2Rs mediate essential interactions between OSCC cells and macrophages, presenting attractive therapeutic targets to stimulate anti-cancer immunity. Our goal is to understand the involvement of T2R pathways in OSCC-macrophage interactions and identify strategies to guide TAMs towards anti-tumor functions rather than tumor-supportive phenotypes. Preliminary data suggests that activation of T2R4 and T2R14 in primary human monocytes and macrophages enhances phagocytosis of OSCC cells. We will further define T2R signaling mechanisms that regulate macrophage-mediated clearance (efferocytosis) of apoptotic OSCC cells through T2R4 and 14 and downstream calcium and nitric oxide signaling. To determine if T2Rs can be targeted/inhibited to guide macrophages phenotypes and support anti- tumor behavior, we will also characterize the effects of T2R4 and 14 stimulation on macrophage polarization (Aim 1). Live cell imaging and biochemical assays will be employed using primary human monocyte-derived macrophages (from healthy donors and patients with OSCC) and patient-derived tumor slice cultures (TSCs). Based on our previously published survival associations from The Cancer Genome Atlas, we hypothesize that T2R signaling influences the pattern of TAM infiltration and oncologic outcomes. We will elucidate how macrophage T2R expression/function affects TAM infiltration and clinical outcomes in human OSCC. Additionally, murine studies will evaluate the effects of T2R agonist treatments on immune cell infiltrates and tumor growth (Aim 2). Uncovering the intricate mechanisms of T2R-mediated interactions in OSCC and macrophages will provide novel insights into therapeutic strategies for enhancing anti-cancer immunity. Project Number: 1R01DE034474-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Ryan Carey | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $511,578 | Activity Code: R01 | Study Section: Tumor Host Interactions Study Section[THI] View on NIH RePORTER: https://reporter.nih.gov/project-details/11225862