Gestational trophoblastic neoplasms (GTN) are rare and aggressive malignancies that arise from trophoblasts, specialized placenta cells whose proliferative and invasive properties are normally essential for pregnancy. Unlike most cancers, GTN originate from allogeneic (foreign) cells that express paternal antigens yet evade immune clearance, challenging basic principles of immunology. Despite their distinct biology and clinical impact, GTN remain understudied with no immune-competent pre-clinical mouse models and little mechanistic insight into how immune tolerance is subverted by the trophoblast cell. While many GTN respond to chemotherapy, drug-resistant cases are often fatal. Early trials targeting the immune molecule PD-L1 hint that immune-based treatments could improve outcomes with fewer side effects, but advancing this potential requires a foundational understanding of GTN immunobiology.

We propose a new framework for understanding the immunobiology of GTN: B cell-driven immune pressure shapes the glycosylation of neoplastic trophoblasts, thereby promoting immune evasion. We are testing the central hypothesis that tumor antigen glycosylation dampens antigen-specific immuen responses, enabling GTN to escape host immunity. A secondary hypothesis is that ongoing immune pressure actively drives glycosylation changes that reinforce this evasion (as depicted in image). The objectives of our study, facilitated by the BioF:GREAT grant and resource center Cycle for Survival, are to (i) perform a comprehensive immune and N-glycan landscape analysis of human GTN, and (ii) characterize the first immune-competent mouse model of trophoblast cancer. This presentation will focus on our early progress, including results showing heightened mouse B cell and antibody responses to trophoblast tumors with altered sialoglycan expression.

Natalia Fuentes

Memorial Sloan Kettering Cancer Center

Appearances