Thymus-derived peptides reduced inflammatory immune activity and improved immunotherapy responses in aged mice, suggesting a potential strategy to address age-related barriers to cancer treatment.
Research: Thymulin suppresses age-related myeloid inflammation and enhances cancer immunotherapy. Image credit: Lightspring
Recent research published in journals nature communications Our results suggest that the thymus-derived peptide thymulin may suppress age-related bone marrow cell inflammation and enhance the response to anti-programmed death ligand 1 (anti-PD-L1) immunotherapy in older mice bearing mammary tumors.
The researchers found that pro-inflammatory myeloid cells were significantly enriched in the mammary tumor microenvironment of older mice, with a higher proportion of myeloid cells in breast tumors from older patients, and increased cytokine production in mice, including tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in human tumors. In mice, these cells were also associated with accelerated disease progression.
As we age, chronic inflammation levels in the body can increase. These age-related inflammatory changes may contribute to cancer development and progression. Older people with these changes may also be less responsive to cancer treatment. A better understanding of the molecular mechanisms underlying these processes could help researchers design more personalized strategies for cancer treatment in older adults.
About research
In the current study, researchers report an age-related increase in bone marrow cells and inflammatory cytokine release in mice and humans. These changes were associated with accelerated breast cancer progression in mouse models, suggesting that targeting myeloid cell-associated inflammation may enhance anti-tumor immune responses.
The research team used metachronous parabiosis, in which young and old mice are surgically joined together to share a common circulation, along with bone marrow chimeras. Metachronous parabiosis allowed us to investigate whether factors circulating in young mouse animals can suppress age-related inflammation, and metachronous bone marrow chimeras helped identify the origin of the factors. Researchers were then able to distinguish between hematopoietic and non-hematopoietic sources.
The researchers also conducted preclinical experiments using a mouse breast cancer model to investigate the effects of systemic factors obtained from young mice on inflammation-related aging, inflammation, and tumor progression. They used AT-3 and E0771 breast cancer cell lines to assess the functional relevance of inflammatory changes. They also performed Ingenuity Pathway Analysis (IPA) to identify candidate molecular mediators of inflammation. Flow cytometry helped quantify cytokine-producing cells.
The researchers then obtained peripheral blood mononuclear cells (PBMCs) from healthy people to quantify cytokine-producing CD33+CD11b+ bone marrow cells and compared the results. They also analyzed single-cell ribonucleic acid sequencing (scRNA-seq) data from 26 primary breast tumors, including 10 triple-negative tumors, 11 estrogen receptor-positive (ER+) tumors, and 5 human epidermal growth factor receptor 2-positive (HER2+) tumors. Those affected ranged in age from 35 to 88 years.
The team then performed differential gene expression analysis to characterize age-related differences. They then performed a luciferase reporter assay to investigate the role of nuclear factor kappa B (NF-κB) signaling in suppressing thymulin-mediated inflammatory cytokine release. They also investigated whether thymulin could enhance the effectiveness of anti-PD-L1 drugs in a mouse model.
result
The research team found that inflammatory processes and myeloid cell populations, including monocytes, granulocytes, macrophages, and dendritic cells, increased with age in the tumor microenvironment of mice and humans. Circulating factors in the bloodstream not derived from the bone marrow of young hosts suppressed this myeloid inflammatory activation. Previous studies have shown that thymulin decreases with age. In this study, the peptide suppressed age-related inflammatory cytokine secretion by inhibiting the NF-κB pathway. This peptide enhanced T-cell activity, improved tumor control, increased tumor sensitization in older mice to PD-L1-targeted drugs, and prolonged survival in these models.
Breast cancer progression was accelerated and survival rates were lower in older mice than in younger mice. Bone marrow cells expressing cluster of differentiation 11b (CD11b), which produces inflammatory cytokines, were more abundant in tumor tissues of older mice. In humans, the frequency of cytokine-producing CD33+CD11b+ bone marrow cells was positively correlated with age. There were more of these cells in people aged 60 to 87 than in people aged 21 to 33.
Human breast cancer datasets showed that genes involved in antigen presentation and bone marrow cell maturation are enriched in bone marrow cells of young individuals. On the other hand, these cells obtained from older patients showed increased expression of inflammatory cytokines, damage-associated molecular pattern (DAMP) molecules, and inflammasomes.
Ingenuity Pathway Analysis identified FOXO3, LMNA, and SIRT family genes as potential inflammatory regulators. Previous studies have associated defects in these genes with increased proinflammatory cytokine release, and thymic atrophy is a common phenotype in related knockout models. These findings gave rise to the hypothesis that thymus-derived systemic factors produced by thymic epithelial cells may help suppress myeloid cell-associated inflammation. In support of this, 1 week of thymulin treatment reduced the frequency of circulating cytokine-producing myeloid cells in old mice. In another experiment, thymulin reduced inflammatory cytokine production and NF-κB p65 DNA binding in lipopolysaccharide (LPS)-activated bone marrow-derived macrophages of aged mice. In IL6 promoter reporter assays, mutation of the NF-κB binding site also abolished the inhibitory effect of thymulin. The peptide also reduced myeloid inflammation and enhanced adaptive immunity by promoting interferon gamma (IFN-gamma) production by tumor-infiltrating CD4+ and CD8+ T cells in aged mice.
conclusion
This finding suggests that the thymus regulates myeloid cell-associated inflammation and that thymulin may suppress the release of inflammatory cytokines by these cells. Additionally, thymulin may enhance the efficacy of immunotherapy drugs and slow tumor growth in older mouse animals. This finding needs to be confirmed in additional models, including different types of cancer, and in human studies.
Further research, including clinical studies, is needed to determine whether thymulin can reduce age-related myeloid inflammation and improve antitumor immunity in older adults.
Reference magazines:
- Hiroshi Kanemaru, Luong, S., Yuya Yamamoto, Yuya Mizukami, Fumiya Ito (2026) Thymulin suppresses age-related myeloid inflammation and enhances cancer immunotherapy. Nature Communications, 17(1), 6534. Doi: 10.1038/s41467-026-75383-0, https://www.nature.com/articles/s41467-026-75383-0
