Tumor microenvironment (TME) generates immunosuppressive niche to induce CD8+ tumor infiltrating lymphocytes (TILs) exhaustion. Therapeutic targeting to functionally reinvigorate CD8+ T cells is a promising strategy to enhance antitumor immunity. While interleukin-2 (IL-2) based therapies cause potent T cell activation and proliferation, the clinical application remains challenging due to short half-life and severe toxicity at therapeutic doses. To address this, we engineered mesenchymal stem cells (MSCs) to successfully proliferate and turn on or off CD8 T cell-preferential IL-2 mutein/Fc fusion protein (SIL2-EMSC) to target cytotoxic T cells in the TME. Peritumoral administration of SIL2-EMSCs permits local production of sufficient SIL2 inside the TME and induces complete tumor regression without adverse toxicity. Mechanistically, SIL2-EMSC remodels the TME that activates and expands preexisting CD8+ TILs. Furthermore, local treatment of SIL2-EMSC elicits systemic antitumor responses for the clearance of distal tumor and metastasis. In advanced tumors, SIL2-EMSCs can overcome resistance to immune check blockade (ICB) and β-lapachone (β-lap) chemotherapy. The therapeutic benefits of SIL2-EMSC were also observed in humanized mouse models. Overall, tumor-targeted delivery of cytokines by next generation of MSCs reverses immunosuppressive environment, improves antitumor effects, and synergize with various therapies without adverse toxicity.
Citation Format: Joonbeom Bae, Longchao Liu, Casey Timmerman, Eric Hsu, Anli Zhang, Jiankun Zhu, Yang-Xin Fu. Tumor-targeted IL-2 by engineered mesenchymal stem cells reinvigorates CD8+ T cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P058.