Why Male Mice Lose Anti-Cancer Immunity Earlier

A new study found that shrinking reserves of naive T cells weaken tumor recognition in male mice by middle age more than in females. Restoring thymic activity improved protection [1].

Do men lose anti-cancer defenses with age?

CD8+ T cells are immune cells that can kill infected or cancerous cells. However, an individual T cell cannot recognize every threat: its T cell receptor only recognizes particular antigens. Therefore, broad immune protection requires a diverse T cell population.

Naive T cells are those that have not yet been activated by their matching antigen. Their initial activation (priming) usually occurs in lymph nodes and depends on the appropriate T cell bumping into an antigen-presenting cell that displays its matching antigen.

This creates a problem: even if the body maintains a diverse collection of T cell receptors overall, a particular lymph node might contain too few cells to reliably include those able to recognize a nearby tumor. This might be one of the reasons why cancer incidence rises with age.

Interestingly, men have higher rates of many cancers, with the gap becoming more pronounced around middle age [2]. A new study from Massachusetts General Hospital, published in Nature Aging, investigates whether differences in how the immune system ages could help explain this disparity – in particular, whether T cell responses against tumors become less efficient in men.

Sex differences emerge

When the researchers implanted melanoma into young and middle-aged mice, tumor growth was similar between young males and females, but middle-aged males controlled it less effectively than middle-aged females did. Depleting CD8+ T cells accelerated tumor growth in both sexes, erasing the female advantage. This established that the difference depended on this particular type of immune cell.

Middle-aged female mice had more tumor-specific and activated CD8+ T cells within their tumors. The next question was where the difference in activation originated. Removing the spleen did not eliminate the female advantage, but using mice without functional lymph nodes did. This implicated lymph nodes as responsible for the stronger female response.

Female tumor-draining nodes, which receive fluid and antigens from the tumor’s location, contained more activated and tumor-specific CD8+ T cells, but there was no evidence of faster proliferation of activated cells. Antigen uptake and presentation by antigen-presenting cells also did not differ significantly between sexes. That pointed toward a different issue: the supply of T cells capable of recognizing the displayed antigen.

Counting specific cell populations indeed showed a substantial absolute loss of naive CD8+ T cells with age. Importantly, male mice started losing these cells earlier than females. Published human blood datasets that the researchers used also suggested an age-related, sex-biased depletion of naive CD8+ cells.

Human CT scans showed smaller lymph nodes in men. Mouse experiments revealed that lymph node size and cell numbers declined earlier in males. Interestingly, receptor diversity was high in both sexes, but a smaller node could retain high relative diversity while still having fewer distinct receptors in absolute terms.

Memory issues

The researchers also found an early male bias toward “virtual memory cells” [3]. When a naive T cell encounters its antigen, it undergoes rapid expansion, with some of its clones becoming cytotoxic CD8+ T cells and some becoming memory T cells. The latter linger in the body, ready to mount a fast immune response against the now familiar threat. Virtual memory cells resemble regular ones but arise from naive T cells without the antigen activation part.

Naive T cells may be slower to respond because they require activation, but they maintain their ability to rapidly expand, while memory T cells gradually lose it with age. The paper’s overarching idea is that the male-specific bias towards naive T cells becoming virtual memory T cells begins to dampen anti-tumor responses later in life.

Indeed, the researchers found that virtual memory cells produced more immune cytokines (signaling molecules) after stimulation but proliferated less effectively. They also showed more senescence-associated gene expression.

The researchers treated young mice with an interleukin-15 (IL-15) complex. In this setting, this cytokine facilitates virtual memory formation. A brief treatment increased the number of virtual memory cells in young females but also caused them to have fewer naive CD8+ T cells seven months later. At this point, but not early after treatment, tumor control was significantly impaired.

The thymus and the testes

The team also investigated the role of the thymus, where T cells mature. With age, this crucial organ shrinks and turns into fat (thymic involution) [4], and this process is known to happen faster in males.

Human imaging and blood measurements linked poorer thymic preservation, which is more pronounced in men, with fewer naive CD8+ T cells. Markers identifying cells recently released from the thymus suggested a relationship between thymic output and the reserve of naive T cells.

The researchers then experimentally depleted immune cells in middle-aged mice. Females rebuilt their naive CD8+ population faster and had more cells that recently originated in the thymus. Thymus removal at six weeks of age eliminated the female advantage.

When challenged with melanoma in middle age, thymectomized females also lost their advantage in tumor control. This suggests that continued thymic function after early life contributes to later protection.

The final experiments asked whether the deficit could be reversed. Knowing that androgens, including testosterone, suppress thymic activity, the researchers reduced androgen signaling through surgical removal of the testes or treatment with degarelix, a drug that suppresses gonadal hormone production.

Androgen suppression increased thymic cellularity, repopulated lymph nodes, and restored naive CD8+ T cell numbers in middle-aged male mice. They had stronger tumor-specific responses and controlled melanoma more effectively, substantially reducing the sex difference.

Literature

[1] Menzel, L., Zschummel, M., O’Melia, M. J., Sandstedt, M., Zhou, H., Lei, P. J., … & Padera, T. P. (2026). Lymph node contraction links sex-biased naive CD8+ T cell decline to compromised antigen recognition during middle age Nature Aging, 1-17.

[2] Cook, M. B., Dawsey, S. M., Freedman, N. D., Inskip, P. D., Wichner, S. M., Quraishi, S. M., … & McGlynn, K. A. (2009). Sex disparities in cancer incidence by period and age Cancer Epidemiology Biomarkers & Prevention, 18(4), 1174-1182.

[3] White, J. T., Cross, E. W., Burchill, M. A., Danhorn, T., McCarter, M. D., Rosen, H. R., … & Kedl, R. M. (2016). Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nature communications, 7(1), 11291.

[4] Araki, T., Nishino, M., Gao, W., Dupuis, J., Hunninghake, G. M., Murakami, T., … & Hatabu, H. (2016). Normal thymus in adults: appearance on CT and associations with age, sex, BMI and smoking. European radiology, 26(1), 15-24.