TGFBI Production by Macrophages Contributes to an Immunosuppressive Microenvironment in Ovarian Cancer

Abstract

The tumor microenvironment evolves during malignant progression with major changes in non-malignant cells, cytokine networks, and the extracellular matrix (ECM). In this study, we aimed to understand how the ECM changes during neoplastic transformation of serous tubal intraepithelial carcinoma lesions (STIC) into high-grade serous ovarian cancers (HGSOC). Analysis of the mechanical properties of human fallopian tubes (FT) and ovaries revealed that normal FT and fimbria had a lower tissue modulus, a measure of stiffness, than normal or diseased ovaries. Proteomic analysis of the matrisome fraction between FT, fimbria, and ovaries showed significant differences in the ECM protein transforming growth factor beta induced (TGFBI -also known as βig-h3). STIC lesions in the fimbria expressed high levels of TGFBI which was predominantly produced by CD163-positive macrophages proximal to STIC epithelial cells. In vitro stimulation of macrophages with TGFβ and IL4 induced secretion of TGFBI, whereas IFNɣ/LPS downregulated macrophage TGFBI expression. Immortalized FT secretory epithelial cells carrying clinically relevant TP53 mutations stimulated macrophages to secrete TGFBI and upregulated integrin αvβ3, a putative TGFBI receptor. Transcriptomic HGSOC datasets showed a significant correlation between TGFBI expression and alternatively activated macrophage signatures. Fibroblasts in HGSOC metastases expressed TGFBI and stimulated macrophage TGFBI production in vitro. Treatment of orthotopic mouse HGSOC tumors with an anti-TGFBI antibody reduced peritoneal tumor size, increased tumor monocytes, and activated β3-expressing unconventional T cells. In conclusion, TGFBI may favor an immunosuppressive microenvironment in STICs that persists in advanced HGSOC. Furthermore, TGFBI may be an effector of the tumorpromoting actions of TGFβ and a potential therapeutic target. Statement of significanceAnalysis of ECM changes during neoplastic transformation reveals a role for TGFBI secreted by macrophages in immunosuppression in early ovarian cancer.Research.

The Transcoelomic Ecosystem and Epithelial Ovarian Cancer Dissemination

“…Finally, TGFß-1 has been shown to be elevated in STIC lesions and to be produced by tumor-associated macrophages (TAMs). P53 mutant secretory cells were found to induce TGFß1 secretion by TAMs, further supporting the p53 signature as a precursor for STIC ( Figure 1B ) ( 39 ). TGF-ß1 secreted by TAMs has been shown to be involved in EOC progression and will be discussed further throughout this review.…”

The Role of the Extracellular Matrix and Tumor-Infiltrating Immune Cells in the Prognostication of High-Grade Serous Ovarian Cancer

“…This gene was found to act both as a tumor promoter or suppressor depending on the tumor microenvironment [ 40 ]. Moreover, it was recently shown to elicit an immunosuppressive microenvironment in advanced HGSOC and mediate tumor-promoting actions of TGFβ and, hence, represents a potential drug target [ 41 ]. In another recent work, the authors demonstrated that TGFBI secreted by tumor-associated macrophages (TAM) promotes HGSOC‘s progression [ 42 ].…”

TGFBI secreted by tumor-associated macrophages promotes glioblastoma stem cell-driven tumor growth via integrin αvβ5-Src-Stat3 signaling

“…Knocking down TGFBI by shRNA largely abrogated the tumor-supportive effect of TAMs compared to shNT. Increased TAM-derived TGFBI has been found in ovarian cancer and is related to tumor growth and dismal prognosis 56 , 57 . TGFBI secreted by TAMs in ovarian cancer contributed to an immunosuppressive TME and promoted cell migration, and meanwhile, anti-TGFBI antibody treatment reduced peritoneal tumor size in the orthotopic mouse model 56 , 57 .…”