Male mice lose tumor-recognizing T cells faster with age; suppressing male sex hormones improved their response to immunotherapy
Male mice lose tumor-recognizing T cells faster with age; suppressing male sex hormones improved their response to immunotherapy
On October 9, 2026, Nature Aging published a study describing how earlier decline of the thymus, the organ that produces new T cells, and depletion of some of these cells reduce the pool of receptors available to recognize tumors in lymph nodes. Temporarily suppressing male sex hormones in middle-aged male mice replenished this pool and improved their response to immunotherapy.
The T-cell response to a tumor begins in a lymph node, where immune cells bring tumor fragments. Naive CD8 T cells are immune cells encountering such a fragment for the first time. A rare group among them must carry a receptor that recognizes the tumor. These cells multiply, and their descendants travel to the tumor. The fewer naive cells there are, the lower the chance of this initial encounter.
The authors compared middle-aged male and female mice, from 9 to 12 months old. They implanted B16-OVA melanoma cells carrying a protein marker that allowed them to track T cells that recognized the tumor. Males had smaller lymph nodes, fewer naive CD8 T cells in those nodes, and faster tumor growth than females. Depleting CD8 T cells eliminated the difference between the sexes. Immune cells from both sexes were equally effective at carrying tumor fragments to lymph nodes and presenting them to T cells. The researchers therefore focused on the receptor pool.
Two processes accounted for the loss of this pool. The thymus produces new naive T cells, and its age-related shrinkage began earlier in male mice. At the same time, some naive CD8 T cells entered a state of “virtual memory” without encountering their specific antigen. These cells have shorter lifespans and leave lymph nodes more often, so the original receptor pool is depleted faster. In human datasets, the authors also found smaller lymph node volumes in men and an age-related decline in the proportion of naive CD8 T cells in the blood.
The researchers then temporarily suppressed male sex hormones in middle-aged male mice. Cell numbers in the thymus increased, and new naive CD8 T cells replenished the lymph nodes. After this pretreatment, the mice showed improved recognition of the tumor antigen and a stronger response to an antibody against PD-1, a receptor that restrains T-cell activity. This effect was weaker in old male mice.