Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer.
Tommy LidströmJoshua CummingRahul GaurLars FrängsmyrIoannis S PaterasMatthias J MickertOskar FranklinMattias N E ForsellNiklas ArnbergMitesh DongreCedric PattheyDaniel ÖhlundPublished in: Cancer immunology research (2022)
Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell-produced protein that was deposited into the ECM of PDAC tumors and detected high circulating levels of gal 4 in PDAC patients. In orthotopic transplantation experiments, we observed increased infiltration of T cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1-/- mice, demonstrating that the effect was mediated by the adaptive immune system. By performing single-cell RNA-sequencing, we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression associated with a higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T cells, and antigen-presenting dendritic cells in tumors with reduced gal 4 expression. Using a co-culture system, we observed that extracellular gal 4 induced apoptosis in T cells by binding N-glycosylation residues on CD3ε/δ. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC.
Keyphrases
- extracellular matrix
- dendritic cells
- poor prognosis
- single cell
- induced apoptosis
- oxidative stress
- endoplasmic reticulum stress
- binding protein
- end stage renal disease
- chronic kidney disease
- emergency department
- ejection fraction
- newly diagnosed
- type diabetes
- stem cells
- signaling pathway
- case report
- cell proliferation
- long non coding rna
- prognostic factors
- high fat diet induced
- patient reported outcomes
- amino acid