Abstract In high-grade serous carcinoma (HGSC) tumors, the immune composition of the tumor microenvironment (TME) is linked to patient outcomes, with the presence of tumor-infiltrating T and B cells correlating with better outcomes, while increased tumor-associated macrophages are associated with a poor prognosis. As nearly all patients with HGSC are treated in a similar fashion, the TME and survival associations can be extended to treatment response and resistance. Although there are reported mechanisms of therapy resistance, none have been translated into FDA-approved therapies. Few studies have assessed the utility of targeting non-DNA damage repair vulnerabilities or improving tumor immune surveillance. Semaphorin 7A (SEMA7A) —a neuroimmune signaling molecule—is a membrane-bound and shed signaling molecule that activates integrin-β1 signaling. In other cancers, SEMA7A is associated with drug resistance, invasion, immune evasion, and promotion of pro-tumor inflammation. SEMA7A confers resistance to detachment-induced apoptosis and immunotherapy. Uncovering the SEMA7A-dependent mechanisms of therapy resistance represents an opportunity to define a novel therapeutic target and improve treatment responses and patient outcomes. Thus, we hypothesize that SEMA7A signaling activates anti-apoptotic and immunosuppressive signaling to promote therapy resistance. Publicly available data shows that high SEMA7A expression correlates with worse progression-free survival (HR: 1. 48, Log-rank p=0. 00087) and overall survival (HR: 1. 41, Log-rank p=0. 025) in patients treated with carboplatin and taxol. Moreover, high expression of both SEMA7A and PD-L1 (an immunosuppressive signaling protein) is associated with worse progression-free survival and overall survival compared to high SEMA7A with low PD-L1 (HR: 1. 63, Log-rank p=0. 00048; HR: 1. 62, Log-rank p=0. 0076, respectively). SEMA7A expression is also correlated with increased macrophage and regulatory T cell infiltration. In vitro assays revealed that SEMA7A expression increases greater than threefold in chemotherapy- and PARPi-resistant HGSC cells. SEMA7A was knocked down (KD) in isogenic therapy-sensitive vs -resistant pairs of human and murine HGSC cell lines to determine how tumor cell expression of SEMA7A mediates cell survival in suspension and in the presence of chemotherapy and/or PARPi. In clonogenic and drug response assays, loss of SEMA7A alone inhibited the growth of therapy-resistant HGSC cells and restored sensitivity to treatment. Immunoblotting was used to dissect SEMA7A-dependent survival signaling and resistance mechanisms. In vivo studies using an immunocompetent murine model of HGSC compared SEMA7A KD to control tumors and revealed that the loss of SEMA7A increased mouse survival (HR: 0. 246, Log-rank p=0. 011). Flow cytometry for used for immune profiling of the control and SEMA7A KD tumors. Our data highlight that SEMA7A is associated with poorer outcomes, therapy resistance, and an immune-suppressed TME. Thus, SEMA7A represents an attractive therapeutic target against therapy-resistant HGSC tumors. Citation Format: Alan Elder, Benjamin Bitler. Discerning mechanisms of semaphorin 7A-mediated therapy resistance and tumor progression in high-grade serous carcinoma of tubo-ovarian origin 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 B049.
Elder et al. (Fri,) studied this question.