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Downregulating testosterone levels enhance immunotherapy efficiency
Luoyang Wang1,2, Guoqiang Jiang1,2, Nan Jing1,2
1Department of Chemical Engineering, Tsinghua University, Beijing, China.
Abstract:
Low response rates to certain tumor types remain a major challenge for immune checkpoint blockade therapy. In this study, we first conducted an integrated biomarker evaluation of bladder cancer patients from confirmatory cohorts (IMvigor210) and found that no significant differences exist between sexes before acceptance of anti-PD-L1 treatment, whereas male patients showed a better response. Thus, we then focused on sex-related changes post anti-PD-L1 treatment and found no obvious impact on the gut microbiota in male mice but a significant decrease in the sex hormone levels. Further, castration dramatically enhanced the antitumor efficacy against murine colon adenocarcinoma in male mice. Moreover, a narrow-spectrum antibiotic, colistin was innovatively used for deregulation of testosterone levels to enhance the immunotherapy efficiency in male mice. These findings indicate that the impact on the sex hormone levels in males may contribute to the sexual dimorphism in response and provide a promising way to enhance immunotherapy efficiency.
Insights
Male patients respond better to immune checkpoint blockade therapy, potentially due to decreased sex hormones. Lowering testosterone levels in male mice enhanced anti-tumor efficacy, suggesting a new immunotherapy approach.
Area of Science:
- Oncology
- Immunology
- Endocrinology
Background:
- Immune checkpoint blockade therapy, including anti-PD-L1, faces challenges with low response rates in specific tumor types.
- Sexual dimorphism in treatment response suggests underlying biological differences, such as hormonal influences, warranting investigation.
Purpose of the Study:
- To investigate the impact of sex on anti-PD-L1 treatment response in bladder cancer patients.
- To explore sex-related changes, particularly sex hormone levels and gut microbiota, in response to anti-PD-L1 therapy in a murine model.
- To evaluate strategies for enhancing immunotherapy efficacy by modulating sex hormone levels.
Main Methods:
- Integrated biomarker evaluation of bladder cancer patients from the IMvigor210 cohort.
- Analysis of sex-related changes in gut microbiota and sex hormone levels in male mice post anti-PD-L1 treatment.
- Assessment of antitumor efficacy following castration and colistin treatment (to deregulate testosterone) in male mice with colon adenocarcinoma.
Main Results:
- Male patients showed a better response to anti-PD-L1 treatment compared to females, with no pre-treatment sex differences observed.
- Anti-PD-L1 treatment in male mice led to decreased sex hormone levels but did not significantly alter gut microbiota.
- Castration and colistin administration significantly enhanced antitumor efficacy in male mice, indicating a role for testosterone.
Conclusions:
- Decreased sex hormone levels in males may contribute to the observed sexual dimorphism in immune checkpoint blockade therapy response.
- Modulating testosterone levels presents a promising strategy to enhance immunotherapy efficiency in male patients.
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