EngineeredMycobacterium smegmatisexpressing anti-PD-L1/IL-15 immunocytokine induces and activates specific antitumor immunity

• DOI: 10.1136/jitc-2024-010118
• Publication Date: 2025-05-22T06:45:22Z
• Authors: Yi Mei; Junmeng Zhu; Jie Shao; Lin Li; Fangcen Liu; Xiaoxuan Sha; Yang Yang; Jie Shen; Rutian Li; Baorui Liu
• Keywords: Mycobacterium smegmatis; Interleukin 15

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