Abstract IA009: Immune suppression in the fallopian tube: Insights from the pre-cancer atlas

Abstract Introduction: Despite the clear genetic evidence linking serous tubal intraepithelial carcinoma (STIC) and high-grade serous ovarian carcinoma (HGSOC), the specific conditions and events that promote the progression of STIC lesions into invasive disease remain poorly understood. Method: As a critical initial step, we have assembled a cohort of incidental p53 signatures (p53. I), incidental STIC (STIC. I), and STIC with concurrent HGSOC (STIC. C). We have performed extensive multi-modal analysis using multiplexed tissue imaging and spatial transcriptomics to identify features of the immune system that play a vital role in the early steps of HGSOC development. We have processed 43 specimens using highly multiplexed tissue imaging at single-cell resolution (cyclic immunofluorescence, CyCIF), and 35 specimens for micro-regional spatial whole transcriptomics using the GeoMx (Nanostring) on over 500 pathologist-annotated regions of interest. Results: We showed a temporal evolution of HGSOC, including the activation of the interferon (IFN) signaling pathway underpinning the progression from the very early stage, p53. I. Additional cancer hallmark pathways, such as Transforming Growth Factor Receptor-β, Hypoxia, were induced in the tumor microenvironment (TME), including STIC. C. One of the mechanisms of the early induction of IFN might be induced by DNA damage response and chromosomal instability, potentially activating the cGAS-STING pathway. We validated IFN activation at the early stage of HGSOC by tissue imaging. For instance, more epithelial cells expressing both HLA-A as well as HLA-E, p-TBK1 and p-STAT3 with disease progression than FT regardless of BRCA status (p0. 001, GLMMs). We found IFN signaling to be persistent at STIC. C and further upregulated in the tumor. To model the evolution of the cancer ecosystem, we then looked into immune composition at both protein and RNA levels. Our data suggested active immune surveillance and potential elimination for p53 signatures. Immune surveillance was potentially further increased at STIC. I by an increased activated cDC1, antigen-presenting cells (APCs), and 30% activated (PD1+) cytotoxic (CD8+ CD103-) and TRM with some level of exhaustion (LAG3+). STIC. C, presumably resembling late clonal expansion, had less intra-tumoral NK and cDC1 in both protein and RNA levels. There was a gradual decline in total CD8+ T cells with HGSOC progression, while 30-40% expressed Ki67/PD1 or LAG3 in cancer, indicating immune editing. Exhaustion state was further shown with HAVCR2 expression (TIM3). We found that one of the contributors of T cells exhaustion was chronic IFN. Conclusion: Epithelial cells with IFN activation seem to be under a natural selection with HSGSOC progression. One of the selective advantages might be the upregulation of MHC-class I. HLA-E upregulation by tumor cells was shown to be immune suppressive by reducing NK cell surveillance. Along with the gradual accumulation of cancer hallmark pathways, an emergence of immune suppressive mechanisms seems to arise at the very early precursor stage. Citation Format: Tanjina Kader, Jia-Ren Lin, Clemens Hug, Shannon Coy, Yu-An Chen, Ino de. Bruijin, Clarence Yapp, Jeremy L. Muhlich, Nikolaus Schultz, Charles W. Drescher, Peter K. Sorger, Ronny Drapkin, Sandro Santagata. Immune suppression in the fallopian tube: Insights from the pre-cancer atlas abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl): Abstract nr IA009.