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Cancer agnostic potential of CAR T cells targeting the urokinase plasminogen activator receptor

ABSTRACT: Chimeric Antigen Receptor (CAR) T cells have demonstrated transformative efficacy in hematologic malignancies and have shown promise in non-cancer contexts such as autoimmune diseases. We previously identified the urokinase plasminogen activator receptor (uPAR) as a cell-surface protein expressed on subsets of myeloid cells and broadly upregulated in senescent states. Murine uPAR-targeting CAR T cells can ameliorate fibrosis and prophylactically prevent metabolic syndrome in aged mice, paving the way for their use in senescence-driven pathologies. uPAR can also be expressed at high levels in cancer and, by performing a pan-cancer analysis, we now show that subsets of most tumor types display strong uPAR expression, which correlates with an epithelial-mesenchymal transition (EMT)-like state, increased fibrosis, metastasis, and poor patient outcomes. Single-cell and spatial analyses revealed that tumors with high uPAR expression in tumor cells often harbor senescent-like, uPAR-positive stromal cells, typically subsets of fibroblasts and macrophages. In mouse models, CAR T cells with uPAR-targeting single-chain variable fragments (scFvs) showed potent and persistent efficacy against multiple tumor types. In the context of high-grade serous ovarian cancer, adjuvant CAR T cell treatment following primary tumor debulking surgery cured mice by eliminating distal organ metastases. uPAR CAR T cells were well-tolerated, demonstrating efficacy in syngeneic and humanized immune system models without significant disruption of the myeloid compartment. Beyond direct tumor targeting, uPAR facilitated non-invasive cancer monitoring via soluble uPAR and PET imaging. Senescence-inducing therapies further enhanced uPAR expression and showed combinatorial activity with uPAR CAR T cells. These findings establish uPAR CAR T cells as a cancer-agnostic therapeutic strategy with a favorable safety profile and clear clinical potential in oncology, including solid tumors harboring a fibrotic tumor microenvironment linked to accumulation of senescent stromal cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293800 | GEO | 2026/03/31

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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Cancer agnostic potential of CAR T cells targeting the urokinase plasminogen activator receptor

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