Study explains why cancer immunity declines faster in males

Lutz Menzel, PhD, formerly of the Department of Radiation Oncology within the Mass General Brigham Cancer Institute, and Tim Padera, PhD, currently of the Mass General Brigham Cancer Institute, are the lead and senior authors of a paper published in Nature Aging, "Lymph node contraction links sex-biased naive CD8 T cell decline to compromised antigen recognition during middle age." The new study combines mouse experiments and human datasets to explore how biological sex and aging shape cancer immunity, with implications for immunotherapy responses.

Q: What challenges or unmet needs make this study important?

Aging is accompanied by a gradual decline in immune function, reducing our ability to mount effective responses against infections and cancer. This presents a particular challenge in the context of cancer immunotherapy, as treatments such as immune checkpoint blockade rely on the immune system's ability to recognize and respond to tumor antigens.

To date, we still do not fully understand why this capacity declines with age. There are also substantial differences between biological women and men in cancer incidence, immunity and responses to immunotherapy, but how biological sex interacts with immune aging remains poorly understood. Gaining a better understanding of how age and biological sex shape anti-cancer immunity could ultimately enable more individualized treatment decisions that account for the state of a patient's immune system.

Q: What central question(s) were you investigating?

Why does anti-cancer immunity change with age, and why does it differ between biological women and men? We investigated these questions through the lens of T cell immunity, immune surveillance and the ability to recognize cancer antigens.

Q: What methods or approach did you use?

We combined experimental mouse models of melanoma with public data from human melanoma patients to examine how age and sex shape T cell immunity.

In female and male mice, we tracked changes in lymph nodes, the thymus (an immune organ where T cells develop and mature) and naive CD8 T cells (newly formed T cells that have not yet encountered a threat) across the lifespan. We then tested how these changes affected the recognition and control of melanoma tumor cells. We complemented these experiments in mice with human imaging and immune-cell datasets to determine whether similar age- and sex-associated patterns occur in people.

Finally, using the mouse models, we manipulated how naive T cells developed into specialized immune cells to test which mechanisms were responsible for the observed differences, and also regenerated thymic function for a short period to test whether anti-cancer immunity can be improved in aging.

Q: What did you find?

We found that the immune system ages differently in biological male and female subjects. In male mice, naive CD8 T cells were lost earlier in life, accompanied by an earlier contraction of the size of lymph nodes. This left fewer T cells locally available to recognize tumor antigens, resulting in impaired anti-cancer immune responses.

Importantly, we found that temporarily reducing the suppressive effects of male sex hormones on the thymus in middle-aged male mice replenished naive CD8 T cells in lymph nodes, improved tumor recognition and enhanced the response to immune checkpoint blockade. Human data supported key aspects of this sex-biased pattern of immune aging, including differences in lymph node size, age-related shrinkage of the thymus and naive CD8 T cells.

Q: What are the real-world implications, particularly for patients?

Our findings suggest that age and sex can shape the immune environment, which can impact cancer outcomes and immunotherapy responses. Understanding these differences could eventually help clinicians better assess a patient's capacity to mount new anti-cancer immune responses and guide more individualized treatment decisions.

This work provides a mechanistic link between thymic function and the ability of the immune system to recognize cancer. This helps explain why it may be important to maintain thymic function well into adulthood and identifies the thymus as a potential target for future strategies aimed at preserving or restoring anti-cancer immunity.

Q: What emerging trends in this field excite you right now?

Recent studies from the Scadden Lab and the Artificial Intelligence in Medicine (AIM) Program of Mass General Brigham have challenged the long-standing view that the thymus becomes largely irrelevant after childhood, showing that thymic health in adults is associated with overall health and outcomes from cancer immunotherapy.

Our study adds a mechanistic perspective by showing how continued thymic output can help maintain the pool of naive T cells available in lymph nodes to recognize cancer antigens. Together, these findings are changing how we think about the adult thymus, from an organ that simply declines with age to one that may remain an important determinant of immune competence throughout life.