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Quiescent tumor cells shape the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma [RNA-Seq]

ABSTRACT: Immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, has limited activity in pancreatic ductal adenocarcinoma (PDAC). Using orthotopic PDAC mouse models, we identified a rare population of quiescent PDAC cells that increases after CAR-T cell therapy and exhibits relatively higher clonogenic growth and self-renewal potential than bulk tumor cells. These quiescent cells express high levels of Epiregulin (EREG), a secreted ligand for EGFR and ErbB4, and induce an immunosuppressive tumor microenvironment by increasing the frequency of ErbB4-expressing tumor-associated macrophages. Silencing EREG expression increased the sensitivity of both quiescent cells and tumors to CAR-T cells and improved relapse rates and overall survival. These findings demonstrate that rare quiescent tumor cells can modulate the tumor microenvironment in PDAC and suggest that EREG inhibition may enhance the efficacy of adoptive immunotherapeutic approaches in this disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE311363 | GEO | 2026/06/17

REPOSITORIES: GEO

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Project description:Anti-cancer immunotherapy approaches are increasingly coveted. Chimeric antigen receptor (CAR)-T cell therapy has been shown to be an effective treatment for hematological tumors, but the treatment of solid tumors still lacks effectiveness, due to lower intra-tumor infiltration of CAR-T cells and tumor-induced immunosuppression. Macrophages represent a very large proportion of the tumor environment, participate in many aspects to tumor development and therefore represent interesting therapeutic targets. Macrophages can infiltrate solid tumor tissue and interact with almost all cellular components in the tumor microenvironment. In addition, macrophages can also promote a direct anti-tumor response by phagocyting tumor cells. We have developed macrophages expressing a CAR receptor against the HER2 antigen. The CAR receptor possesses an intracellular domain CD3ζ having homology with the protein FcεRI-γ, which once activated by the recognition antibody-antigen, induces the phagocytic activity of macrophages. 72% of macrophages express the CAR after transduction. CAR-M can specifically phagocyte HER2 coated-beads in a much more effective way than WT macrophages. We have then confirmed the capacity of CAR-M to phagocyte HER2+ cancer cell lines. Co-culture of CAR-M with breast cancer tumoroids (HER2+ or HER2-) has also been performed demonstrating their efficacy in a more complex environment. However, in the tumor microenvironment, due to their plasticity, macrophages tend to adopt an anti-inflammatory phenotype losing their anti-tumor activities. We have therefore developed a combined strategy by inhibiting two proprotein convertases, Furin and PC1/3 in CAR-M. The inhibition of furin or PC1/3 induces an increase in pro-inflammatory markers and maintains macrophage activation in the presence of cancer cells. In addition, HER2+ CAR-M with shFurin or shPC1/3 greatly increases the phagocytic activity on Her2+ beads or Her2+ tumors. These enzymes are therefore phenotypic regulators of macrophages. Our strategy is therefore based on a double activation of tumor-infiltrating macrophages. The first one consists in boosting the phagocytic activity of macrophages by having them express a CAR receptor targeting a tumor antigen. The second allows their reprogramming towards a pro- inflammatory phenotype by the inhibition of Furin and/or PC1/3 proprotein convertases

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Quiescent tumor cells shape the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma [RNA-Seq]

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