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Updated: May 16, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Enhancing antitumor immunity through chemotherapeutic-derived lipid nanoparticle-induced immunogenic cell death and
Xucheng Hou1, Chang Wang1, Yichen Zhong1
1Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Abstract:
Dendritic cells (DCs) are essential for inducing effective antitumor T cell responses. However, the immunosuppressive tumor microenvironment (TME) hinders DC recruitment and maturation, facilitating tumor progression and spread. This study investigates the synergistic potential of immunogenic cell death (ICD), triggered by chemotherapeutic-derived lipid nanoparticles (LNPs), in combination with Flt3L and CD40L mRNA delivery to enhance DC mobilization and activation, reprogram the TME, and ultimately promote robust antitumor T cell responses. The optimized LNP formulation, GEM5Q7, efficiently delivered mRNA and induced ICD in melanoma cells. Intratumoral administration of GEM5Q7, encapsulating Flt3L and CD40L mRNAs, elevated pro-inflammatory cytokine and chemokine secretion, driving the infiltration and activation of cross-presenting DCs, which are critical for priming T cells. In a subcutaneous melanoma model, this approach led to significant tumor suppression and a 40 % complete response rate. This strategy holds promise for enhancing cancer immunotherapies by reprogramming the TME and inducing durable antitumor T cell immunity.
