Single-cell myeloid diversity in human fallopian tube and its implications for early high grade serous ovarian cancer

Abstract

Abstract The 5-year survival rate of high grade serous ovarian cancer (HGSOC) has remained below 40% for decades. This rises significantly to 90% when detected early. Increasing evidence suggests that HGSOC tumors originate in the fallopian tube (FT). However, little is known about FT’s immune cell heterogeneity and how it contributes to HGSOC development. Here we show a single-cell transcriptome analysis of non-malignant FT samples, revealing high monocyte diversity that is lost in HGSOC. FT monocyte subsets display distinct inflammatory gene signatures such as IL1A, CCL3/4 and others. Trajectory inference showed potential monocyte maturation steps that started with early cytokine/chemokine secreting monocytes that gain MHCII expression and develop into macrophages or dendritic cells. We found the macrophage-to-monocyte ratio is remarkably elevated in tumors compared to adjacent normal ovary and non-cancerous FT tissues in ours and publicly available scRNA-Seq. Intriguingly, analysis of FT of patients with BRCA1/2 germline mutations revealed half of these high-risk individuals are more like those found in HGSOC tumors than in normal FT. They also showed distinct T cell phenotypes in their FTs. Our data suggested that myeloid diversity, and their interactions with T cells in the FT, might contribute to early HGSOC development. Understanding tissue-of-origins immune microenvironment has a potential contribution to early cancer detection. We anticipate this work provides evidence of how myeloid cell plasticity induces tumorigenesis and can shape different tumor microenvironments. Supported by startup grants from UW-Madison School of Medicine and Public Health and UW-Madison Cellular and Molecular Pathology Graduate Training Program travel awards