Investigation of sex-biased differences in anti-cancer immune responses

• Applicant: Professorin Dr. Sonja Loges
• Subject Area: Immunology ; Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429191104

Cancer represents a fundamental threat to public health worldwide and due to the demographic change cancer incidence will even double until 2040. Innovative treatment strategies are therefore urgently warranted in order to decrease cancer mortality especially in the advanced stages in which the majority of patients still die. Cancer immune therapies have revolutionized treatment of cancer and have the potential to convert the deadly into a chronic disease but until now only in a minority of patients. Therefore, there is an urgent need to improve efficacy of cancer immune therapies in order to achieve long-term benefit in more patients. Surprisingly, despite the well-documented fundamental differences between the male and female immune system there is a knowledge gap about gender disparities in anti-cancer immune responses. Moreover, in recent Phase 3 registration trials with immune checkpoint inhibitors (ICI) in different entities, approximately 70% of patients were male. These numbers indicate a substantial imbalance in sex which becomes even more alarming because recent meta-analyses point to a higher efficacy of ICI in male patients. Based on our preliminary data we put forward the hypothesis that testosterone modulates anti-cancer immune responses and that its presence leads to a more sustained anti-tumor CD8+ T cell response upon treatment with anti-PD1 antibodies. We propose an in-depth mechanistic study with Loss- and Gain-of-Function approaches to characterize the effects of testosterone on specific anti-tumor CD8+ T cell responses in baseline and upon PD1 blockade in preclinical models of acute myeloid leukemia and colorectal cancer. Thereby we will gain novel insights into the effects of testosterone on the immune system and pave the road for clinical trials with the aim to increase the number of patients deriving long-term benefit from ICI and possible other immune therapies.

• DFG Programme: Research Units
• Subproject of: FOR 5068: Sex differences in immunity