Engineered Mycobacterium smegmatis expressing anti-PD-L1/IL-15 immunocytokine induces and activates specific antitumor immunity

作者：Yi Mei, Junmeng Zhu, Jie Shao, Lin Li, Fangcen Liu, Xiaoxuan Sha, Yang Yang, Jie Shen, Rutian Li, Baorui Liu · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-010118 · 被引用次数：5 · 研究领域：Immune Cell Function and Interaction、Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses

Background Immune checkpoint inhibitors and cytokines have revolutionized tumor treatment but are still limited by dose-dependent toxicity and efficacy. In situ vaccine platforms based on intelligent microbes are promising therapeutic strategies that sustainably deliver drugs locally without causing severe systemic risks. Methods In this study, we have innovatively engineered a non-pathogenic, adjuvant-acting Mycobacterium smegmatis ( M. smegmatis ) that co-expresses a programmed cell death-ligand 1 (PD-L1) inhibitor and an interleukin-15 (IL-15) cytokine complex containing the interleukin-15 receptor alpha (IL-15Rα) sushi domain (Ms-PDL1scfv-IL15). Results We demonstrate that the fusion protein of PD-L1 inhibitor and IL-15 cytokine systemically binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. The bifunctional Ms-PDL1scfv-IL15 overcomes resistance to PD-L1 blockade, recruits numerous immune cells in situ, induces dendritic cells (DCs) maturation, initiates the M1 antitumor polarization of macrophages, increases the proliferation and activation of natural killer cells and tumor-infiltrating CD8 + T cells, inhibits regulatory T cells, elicits abscopal effects, stimulates rapid tumor regression, prevents metastasis, and leads to long-term survival in several syngeneic tumor mouse models. We also found that the combination of Ms-PDL1scfv-IL15 with granulocyte-macrophage colony-stimulating factor (GM-CSF) synergistically stunted the tumor progress and stasis. M...