Nature Communications | Age-dependent anti-PD-L2 immunotherapy in melanoma

This study reveals significant efficacy of anti-PD-L2 immunotherapy against melanoma in aged hosts, demonstrating a novel mechanism dependent on IL-17 and IFNγ signaling pathways. These findings provide a theoretical basis for personalized immunotherapy strategies in patients of different ages.

 

Literature Overview
This article, 'Anti-PD-L2 immunotherapy is efficacious against melanoma in aged hosts through IL-17 and IFNγ signalling', published in the journal Nature Communications, reviews and summarizes the differences in efficacy of anti-PD-L2 immunotherapy across host ages, revealing its unique mechanism dependency.

Background Knowledge
Immune checkpoint blockade (ICB) therapy has achieved significant progress in cancer treatment, with antibodies targeting PD-1, PD-L1, CTLA-4, and others now widely used in clinical practice. However, despite its effectiveness in some cancers, the overall response rate remains below 15%. Age, as a significant risk factor for cancer, can profoundly affect the immune system and thus alter the efficacy of ICB. PD-L2, another ligand for PD-1, has been suggested in earlier studies to potentially enhance T cell responses, but its role in tumor immunotherapy remains understudied. By employing multiple mouse models, this study systematically analyzes the mechanism of anti-PD-L2 immunotherapy in hosts of different ages, discovering a significantly enhanced therapeutic effect in aged hosts. The study also highlights the key roles of IL-17 and IFNγ signaling pathways, providing new insights for optimizing ICB treatment strategies across age groups and potentially extending to combination therapies with other ICB antibodies.

 

 

Research Methods and Experiments
The research team utilized young and aged wild-type (WT) and gene knockout (KO) mice, including IFNγKO, IL-17KO, and δTCRKO strains. Mice were challenged with tumor models such as B16, NCH1, MB49, and ID8agg, and the immune cell phenotypes and cytokine expression in the tumor microenvironment (TME) were analyzed using flow cytometry. Additionally, UMAP analysis, Ki67 staining, and assessments of CXCR3 and CCR2 expression were employed to evaluate immune cell functionality. Human-derived single-cell RNA sequencing (scRNA-seq) data were also analyzed to determine γδ T cell expression patterns and PD-L2 levels across age groups.

Key Conclusions and Perspectives

• In aged hosts, anti-PD-L2 therapy significantly suppresses the growth of B16 and NCH1 melanomas, whereas it shows no effect in young hosts.
• Anti-PD-L2 treatment in aged hosts enhances infiltration and secretion of IFNγ+ immune cells, a process dependent on the presence of IL-17.
• In aged hosts, γδ T cells are essential mediators of anti-PD-L2 efficacy, and their absence leads to treatment failure.
• Analysis of human γδ T cell scRNA-seq data reveals that Tγδ17 cell proportions increase with age, and PD-L2 expression levels decrease.
• Exogenous IL-17 can render young hosts responsive to anti-PD-L2 therapy, suggesting its potential regulatory role in enhancing anti-PD-L2 efficacy.
• Anti-PD-L2 also shows age-associated enhanced efficacy in different tumor types, such as bladder cancer MB49, but is ineffective in ovarian cancer, indicating tissue-specific effects.
• Anti-PD-L2 enhances the multifunctionality of CD8+ T cells in aged hosts, thereby augmenting their anti-tumor effector functions.

Research Significance and Prospects
This study is the first to reveal the significant efficacy of anti-PD-L2 immunotherapy in aged hosts, identifying its mechanism as being associated with IL-17 and IFNγ signaling pathways. It provides a theoretical foundation for personalized immunotherapy strategies across age groups and suggests that exogenous IL-17 may enhance responses to anti-PD-L2 in young hosts. Future studies may further explore the combination of anti-PD-L2 with other ICB antibodies, such as anti-PD-1 and anti-CTLA-4, and evaluate their age-dependent efficacy across various tumor types.

 

 

Conclusion
This study demonstrates that anti-PD-L2 immunotherapy exhibits significant efficacy against melanoma in aged hosts, with its mechanism relying on the synergistic action of IL-17 and IFNγ signaling pathways. While anti-PD-L2 shows no effect in young hosts, its efficacy can be restored with exogenous IL-17. Additionally, the research identifies γδ T cells as a necessary mediator of anti-PD-L2 efficacy in aged hosts, but not in young ones. Human-derived data further support distinct gene expression profiles and reduced PD-L2 expression in γδ T cells from aged individuals. These findings not only expand our understanding of age-related differences in immune checkpoint therapy responses but also suggest novel intervention strategies to enhance ICB efficacy in younger patients. The research team recommends that future preclinical studies should more closely examine the impact of host age on ICB efficacy and explore modulation of IL-17 signaling to enhance anti-PD-L2 therapeutic outcomes.

 

Carlos O Ontiveros, Myrna G Garcia, Clare E Murray, Jose R Conejo-Garcia, and Tyler J Curiel. Anti-PD-L2 immunotherapy is efficacious against melanoma in aged hosts through IL-17 and IFNγ signalling. Nature Communications.