en
Doctoral thesis
English

The impact of obesity on the response to immune checkpoint inhibitors

Number of pages150
Imprimatur date2024
Defense date2023
Abstract

Immunotherapy has revolutionized the field of cancer research over the last decade, considerably increasing the survival of cancer patients. Immunotherapy aims to re-educate and reinforce the immune system to identify and eradicate cancer cells. One type of immunotherapy, known as immune checkpoint inhibitors (ICIs), has been approved as a first-line treatment for patients with advanced melanoma, metastatic renal cell carcinoma, and lung cancer. The strategy is to target regulatory molecules that restrain the immune system to boost the immune response and prevent cancer evasion. Unfortunately, most cancer patients do not respond to ICIs, which highlights the need to understand the factors that determine ICI efficacy.

Obesity is a major risk factor for cancer incidence and aggressiveness, but recent studies suggest that obese patients with melanoma have a better outcome when treated with ICIs compared to non-obese patients, and this effect was predominantly observed in men. This project aims to investigate the impact of obesity on the antitumor immune response and the efficacy of ICIs in males.

In the first part of the thesis, we compared the efficacy of ICIs between obese and non-obese mice. Male mice fed with a high-fat diet to induce obesity or with a control diet were subcutaneously injected with B16-F10 melanoma cells and treated with anti-PD-1 or control antibodies. Results showed that obesity increases tumor growth, consistent with previous findings. However, ICI treatment reduced tumor growth in obese mice whereas no effect of ICI treatment was observed in non-obese mice, suggesting that obesity may improve ICI efficacy.

The second part focused on the mechanisms behind the increased sensitivity of obese mice to ICI therapy. Since adipose tissue plays an important role in regulating the levels of sex hormones by converting androgens to estrogens, we hypothesized that estrogens could be an obesity-derived factor that improves ICI efficacy. We showed that inhibition of estrogen synthesis blocked the antitumor effect of ICIs in obese male mice. Mechanistically, we demonstrated that adipocyte-derived estrogens increased the differentiation and activation of murine bone marrow-derived dendritic cells, which elicited a strong antigen-specific antitumor immune response.

Lastly, we explored the translational aspect of these findings in a pilot cohort of melanoma patients who received ICI treatment. No relationship was found between body mass index (BMI), estrogen levels, and clinical outcomes in women. However, results showed that overweight and obese men responded better to ICIs than non-obese men. Interestingly, we found that high estrogen levels were associated with a higher chance of ICI response in men but not in women, supporting the hypothesis that estrogens impact ICI efficacy in males. In contrast, no association was observed between obesity or estrogens and patient outcomes in a lung cancer cohort treated with ICIs, highlighting a cancer-specific impact of estrogens.

Overall, our results indicate that the obesity-induced increase in estrogen levels has a significant impact on the efficacy of ICI treatment in men with melanoma. These insights have important implications for the stratification of the ICI-responsive population and suggest that targeting the estrogen pathway may be a promising approach for enhancing the efficacy of cancer immunotherapies.

eng
Keywords
  • Melanoma
  • Immune checkpoint inhibitor
  • Obesity
  • Estrogens
  • Sex
Citation (ISO format)
DUPUYCHAFFRAY, Eloise. The impact of obesity on the response to immune checkpoint inhibitors. 2024. doi: 10.13097/archive-ouverte/unige:175564
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Thesis
accessLevelPrivateaccessLevelPublic 03/31/2025
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Technical informations

Creation02/29/2024 4:51:20 PM
First validation03/13/2024 6:50:10 AM
Update time03/13/2024 6:50:10 AM
Status update03/13/2024 6:50:10 AM
Last indexation05/06/2024 6:09:05 PM
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