PD-1 blockade cancer immunotherapy has been prevailed worldwide as a highly effective new cancer treatment. However, there are still many patients who do not respond to the therapy. Therefore, we need to develop biomarkers and new combination therapy to overcome this problem.

In this study, it is demonstrated that the suppression of naïve CD8+ T-cell differentiation into effector T cells, which plays a central role in the PD-1 blockade therapy, is one of the main mechanisms of the therapy resistance in aged mice. During naive to effector T cell differentiation in response to tumor antigens, CD44^lowCD62L^low (pre-effector-like) CD8+ T cells were induced in young tumor bearing mice. On the other hand, the induction of pre-effector-like cells was significantly suppressed in aged mice with tumors. In the pre-effector-like cells from young mice, the expression levels of genes related to one-carbon (1C) metabolism, which is critical to produce nucleotides and antigen-specific T-cell activation, were upregulated. Surprisingly, strong stimulation by the injection of non-self cells ameliorated the induction of pre-effector-like cells and 1C metabolism in aged CD8+ T cells, and the efficacy of PD-1 blockade therapy in aged mice. These findings provide valuable insights into the mechanism underlying age-related suppression of anti-tumor responses, which may provide a basis for the development of therapeutic strategies for elderly cancer patients. 

Reference:

Yuka Nakajima, Kenji Chamoto, Takuma Oura, Tasuku Honjo. Critical role of the CD44^lowCD62L^low CD8⁺ T cell subset in restoring antitumor immunity in aged mice. Proceedings of the National Academy of Sciences of the United States of America (PNAS), June 4, 2021. DOI: https://doi.org/10.1073/pnas.2103730118