Mentor Name: Todd Hankinson & Siddhartha Mitra

Atypical teratoid/rhabdoid tumor (ATRT) and adamantinomatous craniopharyngioma (ACP) represent two biologically and clinically distinct pediatric brain tumors that lie at opposite ends of the growth and evolutionary spectrum. ATRT is a rapidly proliferative, highly malignant embryonal tumor with poor survival, whereas ACP is a histologically benign but locally aggressive and chronically progressive tumor characterized by slow growth, cyst formation, and significant long-term morbidity. Despite these differences, both tumors exhibit dense myeloid infiltration coupled with ineffective macrophage-mediated tumor clearance, reflecting a shared failure of productive innate immune engagement within the tumor microenvironment. Recent evidence indicates that macrophage phagocytosis is not merely a terminal scavenging process but a powerful instructive event that reprograms macrophage transcriptional, metabolic, and immune states. In both ATRT and ACP, however, macrophages appear locked in poorly phagocytic, tumor-supportive states, suggesting conserved epigenetic constraints that limit macrophage effector function across fast- and slow-growing pediatric brain tumors. The nature of these constraints and whether they can be therapeutically reversed remain poorly defined. Histone deacetylase (HDAC) inhibitors represent a promising strategy to overcome these shared barriers. Beyond direct tumor-intrinsic effects, HDACi remodel chromatin accessibility in innate immune cells, influencing cytoskeletal organization, inflammatory signaling, interferon responses, and antigen presentation pathways. We hypothesize that HDAC inhibition can epigenetically reprogram macrophages to enhance phagocytosis of both ATRT and ACP cells, thereby revealing common immune vulnerabilities despite fundamentally different tumor growth kinetics. This 8-week project, co-mentored by Dr. Siddhartha Mitra, will evaluate how clinically relevant HDACi alter macrophage phagocytic activity and downstream immune programming in vitro. Leveraging Dr. Mitra’s expertise in macrophage biology and pediatric brain tumor immunology, human monocyte-derived macrophages will be co-cultured with ATRT and ACP tumor cells, and changes in phagocytosis following HDAC inhibition will be quantified using flow cytometry–based engulfment assays. We will assess whether HDAC treatment shifts macrophages toward pro-phagocytic, immune-stimulatory states by measuring key regulators of phagocytosis, inflammatory mediators, and antigen presentation machinery. Where feasible, we will explore whether enhanced phagocytosis is associated with activation of interferon-responsive pathways linked to innate immune reprogramming