Galectin-3 synergizes with CD47 to Suppress Phagocytosis and T cell immunity in Peritoneal Metastases of Gastric Adenocarcinoma

Abstract

Peritoneal metastasis (PC), the common sites of gastric adenocarcinoma (GAC) metastasis, remains resistant to therapies available in the clinics and new target is strived to be found. CD47 is one of the major players in conveying the “don’t eat me” signal upon binding its receptor SIRPα on myeloid cells which evade innate immune responses. Previously clinical studies on the blockade of CD47 alone resulted in limited clinical benefits suggesting that other target(s) must be inhibited simultaneously with CD47 for gaining advantage. Here, we found that CD47 was highly expressed on peritoneal malignant cells and its overexpression was a poor prognosticator. Additionally, we observed that Galectin-3 (Gal-3) was highly enriched in tumor cluster and was positively correlated with CD47 expression in short survival of patients revealed by scRNA-seq and metastatic GAC samples. Moreover, we found double positive of Gal-3 and CD47 significantly associated with diffuse type, poor differentiation, and tumor relapse. Mechanistically, Depletion of Gal-3 in mouse tumor and human tumor cells reduced the levels of CD47 through inhibition c-Myc expression and its binding to the promoter of CD47. Additionally, tumor-derived Gal-3 were found critical for tumor progression accompanied with protected GAC cells from phagocytosis by macrophages. Gal-3 deficiency resulted in a marked reduction in M2 macrophages and elevated T cell effector activity. Dual blockade of Gal-3 and CD47 significantly decreased tumor growth by promoted phagocytosis, repolarization of macrophage and boosted T cell immune responses in the tumor microenvironment. Our data uncover that Gal-3 synergizes with CD47 to suppress phagocytosis and orchestrates immunosuppressed milieu in the tumor microenvironment warrants combination therapeutic strategy in GAC patients with peritoneal metastases. Citation Format: Yibo Fan, Shumei Song, Yuan Li, Shilpa Dhar, Jiankang Jin, Xiaodao Yao, Ruiping Wang, Ailing Wang, Melissa Pool Pizzi, Jingjing Wu, Katsuhiro Yoshimura, Lang Ma, Samir Hanash, George Calin, Linghua Wang, Michael Curran, Jaffer Ajani. Galectin-3 synergizes with CD47 to suppress phagocytosis and T cell immunity in peritoneal metastases of gastric adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4433.