Galectin-3 Cooperates with CD47 to Suppress Phagocytosis and T-cell Immunity in Gastric Cancer Peritoneal Metastases
Abstract
The peritoneal cavity is a common site of gastric adenocarcinoma (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to current therapies and confers poor prognosis, highlighting the need to identify new therapeutic targets. CD47 conveys a “don't eat me” signal to myeloid cells upon binding its receptor signal regulatory protein alpha (SIRPα), which helps tumor cells circumvent macrophage phagocytosis and evade innate immune responses. Previous studies demonstrated that the blockade of CD47 alone results in limited clinical benefits, suggesting that other target(s) might need to be inhibited simultaneously with CD47 to elicit a strong antitumor response. Here, we found that CD47 was highly expressed on malignant PC cells, and elevated CD47 was associated with poor prognosis. Galectin-3 (Gal3) expression correlated with CD47 expression, and coexpression of Gal3 and CD47 was significantly associated with diffuse type, poor differentiation, and tumor relapse. Depletion of Gal3 reduced expression of CD47 through inhibition of c-Myc binding to the CD47 promoter. Furthermore, injection of Gal3–deficient tumor cells into either wild-type and Lgals3−/− mice led to a reduction in M2 macrophages and increased T-cell responses compared with Gal3 wild-type tumor cells, indicating that tumor cell–derived Gal3 plays a more important role in GAC progression and phagocytosis than host-derived Gal3. Dual blockade of Gal3 and CD47 collaboratively suppressed tumor growth, increased phagocytosis, repolarized macrophages, and boosted T-cell immune responses. These data uncovered that Gal3 functions together with CD47 to suppress phagocytosis and orchestrate immunosuppression in GAC with PC, which supports exploring a novel combination therapy targeting Gal3 and CD47.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 22, 2023
- Source ID
- 10.1158/0008-5472.can-23-0783
Entities
People
- Ailing W. Scott
- George A. Calin
- Jaffer Ajani
- Jiankang Jin
- Jingjing Wu
- Katsuhiro Yoshimura
- Lang Ma
- Linghua Wang
- Melissa Pool Pizzi
- Michael A. Curran
- Ruiping Wang
- Samir M Hanash
- Shilpa S. Dhar
- Shumei Song
- Xiaodan Yao
- Yibo Fan
- Yuan Li
Organizations
- National Institutes of Health
- The Smith Family
- The University of Texas MD Anderson Cancer Center
- United States Department of Defense
- United States Public Health Service
- University of Texas at Austin