Research Spotlight: Aging Weakens T Cells in the Tumor Microenvironment Making Them Less Effective at Fighting Cancer

Debattama (Deb) Sen, PhD, an assistant investigator in the Krantz Center for Cancer Research in the Mass General Cancer Center and an assistant professor of Medicine at Harvard Medical School, is the corresponding author of a new study in Nature Immunology, The Aged Tumor Microenvironment Limits T Cell Control of Cancer.

Summary:

As people get older, the risk of being diagnosed with cancer increases while the immune system becomes slower to respond. But we don’t fully understand how aging affects the immune system's ability to fight cancer. We studied how aging impacts immune cells called CD8+ killer T cells. We found that as we age, the tumor microenvironment weakens these T cells, making them less effective at fighting cancer. However, we can reinvigorate other helper immune cells, such as myeloid cells, to overcome this defect in aged tumors, offering potential new ways to improve cancer therapy in older individuals.

What Question Were You Investigating?

More than 85% of all cancers occur in individuals aged over 55 years old. However, the research fields of aging, immunology, and cancer have long been isolated from one another. Consequently, our understanding of the impact of aging on anti-tumor immune responses remains limited.

Recent work on the biology of the tumor microenvironment (TME) during aging has shed light on various factors, including the roles of fibroblasts, immunosuppression, and metastasis.

Despite these advancements in our understanding of aging tumor biology, the mechanisms by which aging contributes to defective anti-tumor adaptive immunity, particularly for CD8+ T cells, remain relatively unexplored.

What Were the Results?

To address this question, we examined the relative functions of age-related defects in anti-tumor CD8+ T cells compared to those of the TME in the older tumor-bearing mice.

Our findings suggest that the aged TME diminishes anti-tumor CD8+ T cell effector function and alters T cell differentiation programs, possibly by disrupting communication among natural killer (NK) cells, type 1 conventional dendritic (cDC1) cells, and CD8+ T cells.

Older mice are thereby unable to benefit from the therapeutic mRNA tumor vaccination. Although such age-related defects could not be offset by mRNA vaccine, they could be improved by targeting myeloid populations (including cDC1s) using anti-CD40 agonist antibodies.

This improved tumor control in older mice after CD40 agonism treatment increases intratumoral and tumor-draining lymph node cDC1s, which expressed increased levels of antigen presentation markers. CD40 agonism treatment also reduced the presence of tumor-infiltrating age-associated dysfunctional CD8+ T (TTAD) cells and increased the number of effector-like CD8+ T cell subsets in old mice.

What are the Clinical Implications and Next Steps?

Potential disrupted cell-cell communication among NK cells, cDC1 cells, and CD8+ T cells could explain why the mRNA vaccine is not efficient in older patients but myeloid-mediated therapy (e.g., CD40 agonism treatment) shows promise in correcting these issues in older tumor-bearing mice. Our findings encourage us to further test whether the mRNA cancer vaccine can be combined with myeloid-mediated therapy to improve therapeutic outcomes and also further explore novel therapy options to specifically enhance patient outcomes in older populations.

Paper Cited:

Chen, A. C. Y., Jaiswal, S., Martinez, D., Yerinde, C., Ji, K., Miranda, V., Fung, M. E., Weiss, S. A., Zschummel, M., Taguchi, K., Garris, C. S., Mempel, T. R., Hacohen, N., & Sen, D. R. (2024). The aged tumor microenvironment limits T cell control of cancer. Nature immunology, 10.1038/s41590-024-01828-7. Advance online publication. https://doi.org/10.1038/s41590-024-01828-7