Abstract A042: Onco-fetal immune tolerance factors shape T cell exhaustion and immune evasion in pregnancy and cancer

Abstract Maintaining immune tolerance is central to successful mammalian pregnancy, as the embryo and extraembryonic trophoblasts are semi-allogeneic to the mother. In addition, trophoblasts invade maternal decidua and promote a pro-angiogenic environment to ensure proper blood flow for fetal growth. Interestingly, these key aspects of pregnancy are parallel to host-tumor interaction where cancer cells actively invade host tissue, promote angiogenesis, and exploit tolerogenic features of the immune system to evade host immunity. Despite their significance, previous data analysis approaches have been inadequate in fully elucidating the shared cellular and molecular pathways underlying these processes. By leveraging the power of single-cell RNA-sequencing, we aimed to conduct a comprehensive analysis and comparison of the common cellular and molecular pathways shared between pregnancy and cancer. We integrated publicly available single-cell RNA sequencing datasets from ovarian and cervical cancer, along with decidua under menstrual cycle and first-trimester placental tissues. We uncovered similarities in gene expression profiles and regulatory elements that underlie onco-fetal reprogramming of tumor and placental microenvironment. Specifically, the regulatory signature of CD4+ T cells was commonly increased, yet regulatory T cells themselves displayed enhanced regulatory profiles. In parallel, CD8+ T cell exhaustion signature was increased, with exhausted T cells themselves displaying enhanced exhaustion profiles. Through regulon and network analysis, we identified ETV7 as an onco-fetal driver of CD8+ T cell exhaustion. ETV7 overexpression in chronically stimulated CD8+ T cells enhanced exhaustion phenotypes. Additionally, we found that HLA-C, which is an immune evasion factor highly expressed in cancer cells and extravillous trophoblasts, is commonly regulated by XBP1 in both contexts. Functionally, knockdown of XBP1 reduced HLA-C expression in trophoblasts and cervical cancer cells, and co-culture of XBP1- or HLA-C-knockdown cervical cancer cells with NK cells resulted in increased susceptibility to NK cell killing and enhanced NK cell activation. This study provides comprehensive insights into the immunological challenges in cancer and pregnancy in terms of tolerating foreign entities. Understanding the shared cellular and molecular mechanisms in both contexts may yield valuable insights for developing therapeutic strategies to modulate immune responses in cancer and gestational disorders. Citation Format: Jin Soo Joo, Jongin Kim, Dongeun Lee, Seonyoung Im, Ted Hong, Jun Young Hong. Onco-fetal immune tolerance factors shape T cell exhaustion and immune evasion in pregnancy and cancer [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A042.