Abstract 2141: Exploration of FGL-1 and LAG-3 expression and nivolumab resistance mechanisms in esophageal cancer

Abstract [Background] Anti-PD-1 antibody therapy for esophageal squamous cell carcinoma (ESCC) faces challenges such as low response rates, emphasizing the urgent need to develop novel regimens or predictive biomarkers. Lymphocyte Activation Gene 3 (LAG-3) is an inhibitory immune checkpoint molecule primarily expressed on T cells. It has been demonstrated that combination therapies (anti-LAG-3 and anti-PD-1 antibodies) are more effective than monotherapy (anti-PD-1 antibody) in melanoma. Recently, Fibrinogen-like protein 1 (FGL-1) has been identified as a major ligand for LAG-3. While FGL-1 is secreted from normal hepatocytes, it is known to be secreted in greater quantities by tumor cells in several cancers. FGL-1 that is detectable in peripheral blood holds potential as a biomarker for predicting ICI efficacy and prognosis. However, there are few reports on LAG-3 and FGL-1 in ESCC. [Objectives] To clarify relationship between LAG-3/FGL-1 expression and patient survival or expression of other immune cells in ESCC. To investigate the significance of FGL-1 levels of peripheral blood as a biomarker for ICIs. [Methods] In 316 preoperatively untreated ESCC patients who underwent curative resection, immunohistochemical staining was performed to confirm FGL-1 expression and localization. The relationship between FGL-1 expression, prognosis, and expression of CD3 and CD8 was evaluated.Serum FGL-1 levels were measured using the ELISA method in blood samples before start of treatment of 53 ESCC patients that underwent radical resection. The expression levels were compared with those of healthy controls. In patients with unresectable advanced or recurrent ESCC, plasma FGL-1 levels were measured using the ELISA method before administering anti-PD-1 antibody and evaluated its relationship with treatment efficacy and prognosis. [Results] FGL-1 was localized in tumor cells in ESCC. 121 patients were defined as high FGL-1 expression, which was identified as a poor prognostic factor. However, no correlation was found between FGL-1 expression in tumor cells and the number of T cells. Serum FGL-1 levels were higher in ESCC patients compared to healthy individuals. No association was found between FGL-1 expression in serum and tumor tissue. Plasma FGL-1 levels were significantly higher in the non-responders compared with responders before anti-PD-1 antibody administration. [Conclusions] Using pre-treatment biopsy specimens, FACS analysis will confirm LAG-3+CD8+ T cell expression among tumor-infiltrating lymphocytes, and the relationship with T cell subsets and FGL-1 expression will be evaluated. Citation Format: Hiroki Matsuda, Tomoki Makino, Takafumi Hagi, Kota Momose, Kotaro Yamashita, Takuro Saito, Koji Tanaka, Tsuyoshi Takahashi, Yukinori Kurokawa, Hidetoshi Eguchi, Yuichiro Doki. Exploration of FGL-1 and LAG-3 expression and nivolumab resistance mechanisms in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2141.