Investigating the role of IGF-1 on the anti-cancer immune response

Thesis

Immune cells within the tumour niche can profoundly shape both disease progression and response to anti-neoplastic treatment. In prostate cancer (PCa), developmental pathways are exploited for tumour development, including the insulin-like growth factor-1 (IGF-1) axis. Conversely, fasting-mimicking dietary interventions can enhance anti-tumour immunity, mediated at least in part, by IGF-1 axis inactivation. In this study, the relationship between IGF-1 axis activity and immune cell function was explored in prostate cancer. Using in vitro cell-based assays, the effects of IGF-1 supply on Treg function and metabolism were investigated. Following which, the in vivo effects of combined therapeutic IGF blockade and immune checkpoint blockade (ICB) were evaluated. Then, peripheral blood immune cells were profiled by mass cytometry before and after treatment with an IGF neutralizing antibody, from PCa patients recruited to the WINGMEN trial (NCT05110495). The results from in vitro cell-based assays show that high IGF-1 supply facilitates the metabolic adaptation of regulatory T-cells (Tregs) to high-lactate and low-glucose conditions generated by cancer cells. Subsequent IGF neutralization in murine PCa reduced the frequency tumour-infiltrating Tregs, but did not reduce tumour growth, nor sensitize tumours to ICB. In patients with localized PCa, IGF neutralization boosted peripheral CD8⁺, MAIT and iNKT cell numbers. A low Treg, high memory CD4⁺ T-cell setpoint before treatment initiation correlated with anti-tumour effects from IGF neutralization. In conclusion, this work describes a hitherto unknown link between the IGF-1 axis and tumour-associated Treg metabolism, and defines how reduced IGF-1 levels contribute to anti-tumour immune responses induced by FMD interventions.

Authors: Lang, CR

• DOI: 10.5287/ora-w4e10akyk
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: anti-cancer immunity; regulatory T-cell; IGF-1
• Subjects: Oncology; Immunology