Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Sex-biased immunity

• cancer and aging

• tumour draining lymph nodes

Main Findings

Aging is a major risk factor for disease. Many types of cancer occur in middle-aged to elderly people. This phenomenon is attributed to an increased accumulation of DNA damage over time, which predisposes cells to amass cancer-driving mutations. Further, an aged immune system is less able to control malignant cells and prevent cancer development. Over time, the production of naïve T cells, cross-presentation and antigen uptake by dendritic cells (DCs) decreases, and lymph node architecture degrades. Together, this leads to an overall inferior ability to mount novel T cell responses in aged individuals. In addition to age, biological sex plays a significant role in cancer incidence and survival, with males being more likely to both develop and die of cancer. However, why these factors result in a higher cancer risk in older males is currently unknown. The preprint by Menzel et al. aims to bridge these phenomena by using publicly available human databases and a mouse model of melanoma to investigate cytotoxic T cell responses in the tumour and the lymph node in different age groups. In their experimental setup they describe several main findings:

1. Male mice are worse than female mice at controlling B16 melanoma tumours.

2. Males have a stronger decline in percentage of naïve CD8 T cells with age compared to females in both mice and humans.

3. Male mice are more prone than females to the early formation of virtual memory T cells at the expense of the naïve CD8 T cell compartment.

4. A faster involution of the thymus due to sex steroid hormones in males is responsible for decreased thymic output of naïve CD8 T cells and subsequent lower numbers in the lymph node and lower ability to control tumours.

Limitations & Suggestions

While this preprint was scientifically well conducted, there are some limitations and experiments that could be conducted to increase the relevance of the study and add more mechanistic detail:

• The concept that virtual memory T cells (Tvm) develop sooner in males is described, however the functional relevance of these cells in this context is lacking. In order to strengthen their claim, the authors should include functional data on these cells (e.g. cytokine staining). It would also be informative to assess tumour growth kinetics in female mice treated with IL-15 Cx to assess whether this would reduce their ability to control cancer similar to the males.

• Tt is not explained sufficiently how and why Tvm cells are generated earlier in males. The authors claim it is dependent on IL-15 (as is described in literature) but it is unclear what the increased source of this in males would be. Investigating whether e.g. steroids drive a higher IL-15 production in structural cells of the lymph node would be interesting to explain this phenomenon and to form a more coherent storyline. Along the same line, it would be interesting to measure Tvm cells in their sex-steroid ablation model (SSA; GonX and DeX).

• An additional avenue or discussion point could be how fat impacts the development of Tvms. Fatty tissue is known to be abundant in Tvms and the premature involution of the thymus in males to fatty tissue might be an explanation for the increased presence of these cells specifically in males. There might be a strong metabolic component that is overlooked by focusing only on the known inducer of Tvm, IL-15.

• In their SSA models, the authors describe a rescue effect of thymic output and naïve T cells in the lymph node, and subsequent increased tumour control in males. For this experiment, it is important to have steroid/testosterone treated female mice as a control to evaluate whether the effect seen is a tertiary effect of the absence of these hormones since testosterone has many known effects throughout the body.

• If available/accessible, the claim that sex steroid hormones are a primary cause of a higher cancer risk in aged males could significantly be increased in its clinical relevance by including incidence of cancers in transgender people that are on hormone-replacement therapy.

Significance/Novelty

The individual findings of this preprint are not very novel. Increased risk for cancer, thymic involution, and a decrease in naïve T cells in the elderly, and especially males, are known phenomena. However, taken together the authors are able to connect these findings in a novel way by adding some mechanistic insight on an immune cell level. Investigating sex-specific immune responses is extremely clinically relevant and this preprint gives important information on specific T cell subsets that may be responsible for re-evaluating therapeutic options based on biological sex.

Credit

Reviewed by Teresa Neuwirth as part of a cross-institutional journal club between the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the University of Virginia, the Medical University of Vienna and other life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review.