Abstract A094: CAF-derived MFAP5 enhances immune escape through up-regulating immune checkpoint mediator CD47 in ovarian cancer cells and CD8+ T cells
Authors: Ferri-Borgogno Sammy , Yeung Tsz-Lun , York Emily , Talor Marina , Pacheco Yadira , Nurieva Roza , Birrer Michael , Mok Samuel 
Published: March 2024

Abstract
High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. Most patients with HGSC are diagnosed at advanced stages. HGSC is notable sensitive to platinum/taxane-based chemotherapy. Despite the high response rate, most of these patients will develop recurrent chemoresistant disease. Recent studies showed the cancer associated fibroblasts (CAFs) in the tumor microenvironment (TME) play an important role in modulating the malignant phenotypes of HGSC. CAFs are primarily responsible for producing factors such as cytokines and growth factors to modify the TME niche to promote the malignant phenotypes of cancer cells. Over-expression of MFAP5 in CAFs has recently been shown to be associated with poor prognosis in ovarian cancer. MFAP5 can bind αvβ3 integrin to enhance chemoresistant, and metastatic potential of HGSC cells. Silencing MFAP5 in CAFs suppressed ovarian cancer growth, metastasis, and angiogenesis in vitro and in vivo. In addition, increased stromal MFAP5 expression was associated with decreased density of activated CD8+ cytotoxic T lymphocytes (CTLs) in HGSC samples. Inhibiting MFAP5 by a novel blocking monoclonal antibody (Ab) 130A that we developed in a syngeneic HGSC-bearing mouse model significantly increased intraepithelial CD8+ T cell density, and recombinant MFAP5 increased apoptosis in cultured CD8+ T cells. Despite these findings, the role of MFAP5 in modulating CD8+ T cell activity remains unknown. To determine the molecular mechanism by which MFAP5 modulate immune surveillance in the ovarian TME, transcriptomic profiling was performed on MFAP5 treated HGSC cells and CD8+ T cells. The results showed a marked increase in the expression of CD47, an immune checkpoint mediator that triggers inhibitory “don’t eat me” signaling through SIRPα on macrophages (Mfs), in both MFAP5-treated HGSC cells and CD8+ T cells. Reported assays on HGSC and CD8+ T cells transfected with the CD47 promoter sequence harboring the wild-type or mutated potential MFAP5-response elements ligated to the luciferase construct showed strong luciferase activity in cells transfected with the wild-type but not the mutated constructs, suggesting that those CD47 is transcriptionally regulated by MFAP5 through those elements. Further studies showed a significant correlation between higher CD47 expression in HGSC cells, higher MFAP5 expression in CAFs, worse patient survival rates, and lower intraepithelial CD8+ CTL density. In addition, the pro-apoptotic effect of MFAP5 on recombinant MFAP5-treated CD8+ T cells was abrogated by pre-treating cells with CD47 neutralizing Ab, suggesting that CAF-derived MFAP5 regulates the activation/survival/function of CD8+ T cells in a CD47-dependent manner. In conclusion, our findings demonstrate the role of CD47 mediating the immune suppressive effect of CAF-derived MFAP5 in the ovarian TME. Further studies to identify novel therapeutic strategies to target MFAP5 alone or in combination with immune checkpoint inhibitors to enhance immune surveillance in HGSC are warranted.
Citation Format: Sammy Ferri-Borgogno, Tsz-Lun Yeung, Emily York, Marina Talor, Yadira Pacheco, Roza Nurieva, Michael Birrer, Samuel Mok. CAF-derived MFAP5 enhances immune escape through up-regulating immune checkpoint mediator CD47 in ovarian cancer cells and CD8+ T cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A094.