Illustration realized in the framework of a collaboration between the Image/Recit option of the HEAD (Haute École d'Art et de Design) - Genève and the Faculty of Sciences of the University of Geneva.

Over the last decades, cancer immunotherapy has brought new hope to patients by significantly improving survival. Contrary to chemotherapy and radiotherapy that target cancer cells, immunotherapy aims to strengthen the immune system to recognize and destroy cancer cells. However, while some patients respond very well to immunotherapy, others do not benefit at all. Understanding why is essential to improving cancer treatment for everyone.

A surprising observation in recent years is that obesity—although a major risk factor for many cancers—appears to improve the effectiveness of immunotherapy in patients with advanced melanoma, a common form of skin cancer. Therefore, we investigated the impact of obesity on the efficacy of cancer immunotherapy.

To investigate this, we used a mouse model to be able to study the interactions between the immune system, fat tissue, and cancer. We first compared the effect of immunotherapy on cancer development between obese and lean mice, and we investigated the mechanisms behind the differences in treatment efficacy. We confirmed our findings with in vitro models using cells from fat tissue, immune cells, and cancer cells. Finally, we assessed the translational impact of our findings in a cohort of patients with melanoma and treated with immunotherapy at the Geneva hospital.

We first observed that obese mice developed larger tumors than non-obese mice, which was expected since obesity is a major risk factor for cancer. However, when treated with immunotherapy, only the obese mice showed a slowing of cancer growth, while lean mice did not respond to the treatment. Interestingly, these results were not observed in female mice; females responded to immunotherapy regardless of whether they were lean or obese. Therefore, we hypothesized that estrogens could play a role in the efficacy of immunotherapy. Indeed, fat tissue can transform testosterone into estrogens, resulting in high levels of circulating estrogens in obese males compared to lean males. To verify our hypothesis, we blocked the production of estrogens in obese males. When we did so, tumors grew faster and immunotherapy no longer worked, suggesting that estrogens were indeed supporting the treatment’s effectiveness. We then investigated how obesity-related estrogens improve the effect of immunotherapy and found that estrogens enhance the activity of dendritic cells. These immune cells act as sentinels: they detect cancer, activate other immune cells, and coordinate the body’s anticancer response. By boosting dendritic cell activation, estrogens help strengthen the immune attack triggered by immunotherapy.

To translate these findings to patients, we studied the relationship between obesity, estrogens, and survival of cancer patients treated for melanoma with immunotherapy. Among men, those who responded best to immunotherapy were mostly overweight or obese, whereas few lean men benefited from the treatment. In contrast, women responded equally well regardless of body weight. Next, we measured the levels of estrogens in the blood of these patients, and we observed that higher estrogen levels in men were associated with prolonged survival. This association was not observed in women. 

Overall, we showed that not only obesity but also high levels of estrogens were associated with an increased efficacy of cancer immunotherapy, in male mice and men with melanoma. Our work identifies a key role for estrogens in boosting the antitumor immune response by promoting effective dendritic cell activation. However, further investigation is required to elucidate the detailed mechanisms before being able to develop estrogen-based therapies to treat cancer patients. Notably, we need to understand whether the effect of estrogens on dendritic cells is the only mechanism involved, or whether estrogens play other roles in the anticancer immune response. We also need to understand why the effects of obesity and estrogens are restricted to men, and, for now, to melanoma patients. Meanwhile, this work opens the path to identifying the patients who are more likely to respond to immunotherapy, at least in men with melanoma, so more patients can benefit from these cancer treatments.