Journal for immunotherapy of cancer · 2026
Anti-CTLA-4 antibody potentiates the antitumor effect of armed oncolytic virus OVM18 via enhancing intratumoral IL-18R1+CD8+ T cells.
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Lin Xueying, Zhang Jifu, Fan Zhen, Yang Jingyu, Yi Shiming, Wang Hanrui, Zou Huizhen, Hu Linyi, Zhu Wenbo, Lin Yuan, Hu Jun, Cai Jing, Yan Guangmei, Liang Jiankai
Аннотация
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.
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.