Faculty, Staff and Student Publications
Publication Date
7-1-2024
Journal
Gastroenterology
Abstract
Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a desmoplastic tumor stroma and immunosuppressive microenvironment. Galectin-3 (GAL3) is enriched in PDAC, highly expressed by cancer cells and myeloid cells. However, the functional roles of GAL3 in the PDAC microenvironment remain elusive.
Methods: We generated a novel transgenic mouse model (LSL-KrasG12D/+;Trp53loxP/loxP;Pdx1-Cre;Lgals3-/- [KPPC;Lgals3-/-]) that allows the genetic depletion of GAL3 from both cancer cells and myeloid cells in spontaneous PDAC formation. Single-cell RNA-sequencing analysis was used to identify the alterations in the tumor microenvironment upon GAL3 depletion. We investigated both the cancer cell-intrinsic function and immunosuppressive function of GAL3. We also evaluated the therapeutic efficacy of GAL3 inhibition in combination with immunotherapy.
Results: Genetic deletion of GAL3 significantly inhibited the spontaneous pancreatic tumor progression and prolonged the survival of KPPC;Lgals3-/- mice. Single-cell analysis revealed that genetic deletion of GAL3 altered the phenotypes of immune cells, cancer cells, and other cell populations. GAL3 deletion significantly enriched the antitumor myeloid cell subpopulation with high major histocompatibility complex class II expression. We also identified that GAL3 depletion resulted in CXCL12 upregulation, which could act as a potential compensating mechanism on GAL3 deficiency. Combined inhibition of the CXCL12-CXCR4 axis and GAL3 enhanced the efficacy of anti-PD-1 immunotherapy, leading to significantly inhibited PDAC progression. In addition, deletion of GAL3 also inhibited the basal/mesenchymal-like phenotype of pancreatic cancer cells.
Conclusions: GAL3 promotes PDAC progression and immunosuppression via both cancer cell-intrinsic and immune-related mechanisms. Combined treatment targeting GAL3, CXCL12-CXCR4 axis, and PD-1 represents a novel therapeutic strategy for PDAC.
Keywords
Animals, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Galectin 3, Tumor Microenvironment, Disease Progression, Mice, Humans, Receptors, CXCR4, Disease Models, Animal, Cell Line, Tumor, Gene Deletion, Mice, Transgenic, Programmed Cell Death 1 Receptor, Mice, Knockout, Immune Checkpoint Inhibitors, Immunotherapy, Signal Transduction, Galectins, Pancreatic cancer, Tumor microenvironment, Galectin-3, Single-cell RNA-sequencing, Genetically engineered mouse models
DOI
10.1053/j.gastro.2024.03.007
PMID
38467382
PMCID
PMC11972442
PubMedCentral® Posted Date
4-6-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Gastroenterology Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons