Galectin-3 Cooperates with CD47 to Suppress Phagocytosis and T-cell Immunity in Gastric Cancer Peritoneal Metastases

The peritoneal cavity is a common site of gastric adenocarcinoma Furthermore, injection of Gal3–deficient tumor cells into either (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to wild-type and Lgals mice led to a reduction in M2 macrophages current therapies and confers poor prognosis, highlighting the and increased T-cell responses compared with Gal3 wild-type need to identify new therapeutic targets. CD47 conveys a “don’t tumor cells, indicating that tumor cell–derived Gal3 plays a more eat me” signal to myeloid cells upon binding its receptor signal important role in GAC progression and phagocytosis than host-regulatory protein alpha (SIRPa), which helps tumor cells circumderived Gal3. Dual blockade of Gal3 and CD47 collaboratively vent macrophage phagocytosis and evade innate immune suppressed tumor growth, increased phagocytosis, repolarized responses. Previous studies demonstrated that the blockade of macrophages, and boosted T-cell immune responses. These data CD47 alone results in limited clinical benefits, suggesting that other uncovered that Gal3 functions together with CD47 to suppress target(s) might need to be inhibited simultaneously with CD47 to phagocytosis and orchestrate immunosuppression in GAC with PC, elicit a strong antitumor response. Here, we found that CD47 was which supports exploring a novel combination therapy targeting highly expressed on malignant PC cells, and elevated CD47 was Gal3 and CD47. associated with poor prognosis. Galectin-3 (Gal3) expression correlated with CD47 expression, and coexpression of Gal3 and CD47 Significance: Dual inhibition of CD47 and Gal3 enhances was significantly associated with diffuse type, poor differentiation, tumor cell phagocytosis and reprograms macrophages to overcome and tumor relapse. Depletion of Gal3 reduced expression of CD47 the immunosuppressive microenvironment and suppress tumor through inhibition of c-Myc binding to the CD47 promoter. growth in peritoneal metastasis of gastric adenocarcinoma.