IL‑18 improves the expansion and functional fitness of human Vδ1 T cells for superior solid tumor immunotherapy

Abstract Background Human Vδ1 T cells represent promising candidates for allogeneic adoptive immunotherapy due to their MHC-independent tumor recognition and inherent tissue tropism. However, their clinical translation is hampered by their low frequency in peripheral blood and the challenge of generating sufficient functional cells for therapy. While IL-18 is a well-known modulator of T cells and NK cells, its specific role in regulating Vδ1 T cell biology remains poorly defined. Methods Primary human Vδ1 T cells were magnetically isolated and expanded with anti-CD3 monoclonal antibody and IL-15, in the presence or absence of IL-18. To elucidate the effects of IL-18, we systematically evaluated proliferation kinetics, immunophenotype, and cell viability by flow cytometry. In vitro functional capacity was assessed through tumor cytotoxicity assays, cytokine production, apoptosis, and migration assays. Transcriptional alterations were characterized by RNA sequencing and reverse transcription quantitative PCR (RT-qPCR). Finally, the therapeutic efficacy of IL-18 Vδ1 T cells was assessed in an A549 lung carcinoma xenograft model. Results IL-18 improved the manufacturability of human Vδ1 T cells by significantly accelerating cell-cycle progression and promoting robust clonal expansion while maintaining high Vδ1 T-cell purity. IL-18-expanded Vδ1 T cells exhibited enhanced survival during prolonged tumor exposure, inflammatory cytokine production, and tumor-directed migration, despite reduced contact-dependent cytotoxicity in vitro. Importantly, these cells mediated improved tumor suppression in vivo and significantly prolonged the survival of A549 tumor-bearing mice compared with control Vδ1 T cells. Conclusions IL-18 serves as an important modulator of Vδ1 T cells that enhances their expansion, cellular longevity, and in vivo antitumor efficacy. These findings provide a strategy with translational potential for optimizing the manufacture and therapeutic potential of Vδ1 T cells for solid tumor immunotherapy.