Xueying Lin, Jifu Zhang, Zhen Fan, Jingyu Yang, Shiming Yi, Hanrui Wang, Huizhen Zou, Linyi Hu, Wenbo Zhu, Yuan Lin, Jun Hu, Jing Cai, Guangmei Yan, Jiankai Liang
Our findings establish IL-18R1+CD8+ T cells as an important effector population in OVM18 therapy, thereby providing a strong rationale for combining OVM18 with CTLA-4 blockade to overcome therapeutic resistance and achieve durable antitumor responses.
BACKGROUND: Oncolytic virus M1 encoding a mutant IL-18 decoy (OVM18) represents a novel virotherapy that integrates selective oncolysis with localized activation of the IL-18 pathway. However, the heterogeneity of therapeutic responses suggests that host immune determinants influence its efficacy.
METHODS: To elucidate these determinants, we performed integrated immune profiling using bulk and single-cell transcriptomics, flow cytometry, and T cell receptor (TCR) repertoire analyses. The functional contribution of specific immune subsets was validated using Batf3⁻/⁻ mice and FTY720-mediated lymphocyte trafficking blockade. Potential synergistic immunotherapies were identified through transcriptomic database screening and confirmed in tumor-bearing mice receiving combined OVM18 and immune checkpoint blockade.
RESULTS: We identified intratumoral IL-18R1+CD8+ T cells as an important effector population, whose IL-18R1 expression and intratumoral abundance positively correlate with OVM18 efficacy. Integrated single-cell RNA-sequencing and cytometry analyses revealed that IL-18R1+CD8+ T cells are clonally expanded, tumor antigen-enriched, polyfunctional cytotoxic T cells. Their generation requires conventional type 1 dendritic cells (cDC1)-dependent priming within tumor-draining lymph nodes, followed by trafficking into tumors to mediate antitumor responses. Notably, CTLA-4 blockade enhances cDC1-derived IL-12 and promotes IL-18R1+CD8+ T-cell expansion, thereby overcoming resistance to OVM18 therapy. Combination treatment with OVM18 and anti-CTLA-4 enhances intratumoral IL-18R1+CD8+ T cell infiltration, delays tumor progression, and prolongs survival in poor-responsive models.
CONCLUSIONS: Our findings establish IL-18R1+CD8+ T cells as an important effector population in OVM18 therapy, thereby providing a strong rationale for combining OVM18 with CTLA-4 blockade to overcome therapeutic resistance and achieve durable antitumor responses.