Frontiers in immunology · 2026
Antigen-scaffolds loaded with hyper-stable neoleukin-2/15 expand antigen-specific T cells with a favorable phenotype for adoptive cell therapy.
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Ormhøj Maria, Munk Kamilla Kjærgaard, Tvingsholm Siri, Ramanathan Keerthana, Bentzen Amalie Kai, Kladis Georgios, Aasbjerg Gitte Nygaard, Nos Grigorii, Tamhane Tripti, Halldórsdóttir Hólmfridur Rósa, Jakobsen Søren Nyboe, Frej Marcus Svensson, Johansen Kristoffer Haurum, Kadivar Mohammad, Hadrup Sine Reker
Аннотация
INTRODUCTION: Adoptive cell therapy (ACT) has shown promising results in cancer treatment, however, achieving effective ex vivo expansion of potent, functionally active, and cytotoxic T cells remains challenging. To address this challenge, we recently developed artificial antigen-presenting scaffolds (Ag-scaffolds) capable of expanding antigen-specific T cells with phenotypes favorable for ACT. Here, we compared the established technology using IL2/IL21-loaded Ag-scaffolds (Ag-IL2/21) with scaffolds incorporating Neoleukin-2/15 (Ag-Neo2/15), an engineered cytokine that selectively signals via IL-2Rβ/γ complexes to enhance CD8+ T cell proliferation while limiting regulatory T cell expansion.
METHODS: Antigen-specific T cells were expanded ex vivo using Ag-IL2/21 or Ag-Neo2/15 scaffolds. Expansion efficiency, cytokine production, and cytotoxic activity were assessed. Functional and transcriptional states were profiled using single-cell sequencing, including cytotoxic and dysfunction gene signature scoring. T cell receptor (TCR) sequencing was performed to evaluate clonal expansion.
RESULTS: Ag-Neo2/15 scaffolds supported robust expansion of antigen-specific CD8+ T cells at levels comparable to Ag-IL2/21 scaffolds. Ag-Neo2/15-expanded CD8+ T cells exhibited increased effector cytokine production and durable cytotoxicity against tumor cells. Single-cell transcriptomic analysis revealed higher cytotoxic gene signature scores, reduced dysfunctional scores, and increased expression of genes linked to increased proliferation in Ag-Neo2/15-expanded T cells. TCR sequencing demonstrated preferential expansion of CD8+ T cell clones enriched for transcriptional features associated with antigen-experienced effector states and sustained effector function.
DISCUSSION: Ag-Neo2/15 scaffolds enhance the quality of ex vivo-expanded antigen-specific T cells by promoting a cytotoxic, less dysfunctional, and highly proliferative phenotype. These findings identify Ag-Neo2/15 as a promising improvement for ACT manufacturing, optimizing the balance between expansion capacity and durable effector function, with potential implications for improving cancer immunotherapy outcomes.
METHODS: Antigen-specific T cells were expanded ex vivo using Ag-IL2/21 or Ag-Neo2/15 scaffolds. Expansion efficiency, cytokine production, and cytotoxic activity were assessed. Functional and transcriptional states were profiled using single-cell sequencing, including cytotoxic and dysfunction gene signature scoring. T cell receptor (TCR) sequencing was performed to evaluate clonal expansion.
RESULTS: Ag-Neo2/15 scaffolds supported robust expansion of antigen-specific CD8+ T cells at levels comparable to Ag-IL2/21 scaffolds. Ag-Neo2/15-expanded CD8+ T cells exhibited increased effector cytokine production and durable cytotoxicity against tumor cells. Single-cell transcriptomic analysis revealed higher cytotoxic gene signature scores, reduced dysfunctional scores, and increased expression of genes linked to increased proliferation in Ag-Neo2/15-expanded T cells. TCR sequencing demonstrated preferential expansion of CD8+ T cell clones enriched for transcriptional features associated with antigen-experienced effector states and sustained effector function.
DISCUSSION: Ag-Neo2/15 scaffolds enhance the quality of ex vivo-expanded antigen-specific T cells by promoting a cytotoxic, less dysfunctional, and highly proliferative phenotype. These findings identify Ag-Neo2/15 as a promising improvement for ACT manufacturing, optimizing the balance between expansion capacity and durable effector function, with potential implications for improving cancer immunotherapy outcomes.