Genetic Deletion of Galectin-3 Inhibits Pancreatic Cancer Progression and Enhances the Efficacy of Immunotherapy

Daowei Yang; Xinlei Sun; Rohan Moniruzzaman; Hua Wang; Citu Citu; Zhongming Zhao; Ignacio I Wistuba; Huamin Wang; Anirban Maitra; Yang Chen

doi:10.1053/j.gastro.2024.03.007

Genetic Deletion of Galectin-3 Inhibits Pancreatic Cancer Progression and Enhances the Efficacy of Immunotherapy

Gastroenterology. 2024 Mar 11:S0016-5085(24)00288-9. doi: 10.1053/j.gastro.2024.03.007. Online ahead of print.

Authors

Daowei Yang¹, Xinlei Sun¹, Rohan Moniruzzaman², Hua Wang³, Citu Citu⁴, Zhongming Zhao⁴, Ignacio I Wistuba⁵, Huamin Wang⁶, Anirban Maitra¹, Yang Chen⁷

Affiliations

¹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
² Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
³ Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁴ Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas.
⁵ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁶ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁷ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: ychen23@mdanderson.org.

PMID: 38467382
DOI: 10.1053/j.gastro.2024.03.007

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-Kras^G12D/+;Trp53^loxP/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: Galectin-3; Genetically Engineered Mouse Models; Pancreatic Cancer; Single-Cell RNA-Sequencing; Tumor Microenvironment.