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Engineering an in vivo charging station for CAR-redirected invariant natural killer T cells to enhance cancer therapy

ABSTRACT: Invariant natural killer T (iNKT) cells are a distinct subset of T lymphocytes that possess unique properties making them highly suitable for addressing the challenges of solid tumor immunotherapy. Unlike conventional T cells, which are restricted by polymorphic major histocompatibility complex (MHC) molecules and recognize peptide antigens, iNKT cells are restricted by the non-polymorphic CD1d molecule and respond to lipid antigens. Chimeric antigen receptor (CAR)-redirected iNKT (CAR-iNKT) cells represent a significant advancement in cancer immunotherapy. However, optimizing sustained activation and long-term persistence of CAR-iNKT cells remains a critical need for effective solid tumor treatment. To address these limitations, we develop the iNKT cell-targeted microparticle recruitment and activation system (iMRAS), a biomimetic platform designed to enhance iNKT cell functionality through localized immunostimulation in vivo. This biomimetic platform is designed to function as an in vivo “charging station” containing chemotactic and activation signals for the recruitment, activation, and expansion of CAR-iNKT cells, leading to more effective tumor killing and longer persistence of CAR-iNKT cells, as demonstrated in the therapy of lymphoma and melanoma. Through its biomimetic design and localized immunostimulatory effects, iMRAS helps overcome the limitations of current therapies for solid tumors, establishing a robust platform for enhancing systemic CAR-iNKT cell-mediated immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291443 | GEO | 2025/05/07

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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Engineering an in vivo charging station for CAR-redirected invariant natural killer T cells to enhance cancer therapy

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