Researchers have discovered that treatment of breast cancer with a checkpoint inhibitor drug, called anti-PD-1, significantly reduces obesity-associated tumour burden.
Obesity is associated with both an increased risk of developing breast cancer and a worse prognosis after disease onset. This is because higher levels of hormones that are associated with obesity, such as oestrogen and testosterone, influence cancer growth. Also, obesity accelerates tumour microenvironment dysfunction through the action of microbes, growth factors and immune cells.
Immune checkpoints are part of the immune system – they prevent immune responses from destroying healthy cells. Programmed death-1 (PD-1) is a checkpoint protein that is expressed predominantly by T cells. Tumours can evade the immune system through the overexpression of these checkpoint proteins, leading to a decreased anti-tumour immune response.
Checkpoint inhibitor drugs are a type of immunotherapy that block checkpoint proteins and promote the attack of cancer cells by T cells. Although obstructing immune checkpoints, such as PD-1, has fewer side effects than chemotherapy, many patients fail to respond to the treatment. However, there is a growing amount of evidence to suggest that obese patients respond better to immunosuppressive therapy, particularly in melanoma, non-small cell lung cancer and renal cell carcinoma.
Anti-PD-1 in obese breast cancer patients
Until recently, the impact that weight-based factors play on immune checkpoint therapies in breast cancer remained unknown. Researchers from the University of Tennessee Health Science Centre compared breast cancer tumour progression and immune reprogramming in lean and obese mice, some of which were treated with an immune checkpoint blockade called anti-PD-1. Regulators of the gut and microbiome were also investigated due to their link to obesity and potential association with breast cancer risk and response to therapy.
The findings were as follows:
- Tumour burden, that was increased by obesity, was reduced by anti-PD-1.
- Anti-PD-1 increased tumour regression in the lean mice.
- Anti-PD-1 reversed immunosuppression in the tumour microenvironment of the obese mice.
- Obesity and anti-PD-1 affected pathways and immune infiltrates associated with cancer progression in tumour-adjacent adipose tissue of the mammary fat pad.
- Obesity and anti-PD-1 immunotherapy shaped the gut microbiome. Microbes were correlated with tumour size.
Essentially, the results showed that although obesity accelerated tumour progression, treatment with anti-PD-1 significantly reduced the tumour burden associated with this obesity. Moreover, gut microbes were identified that correlated with tumour size and immune checkpoint blockade efficiency – patients who responded to anti-PD-1 therapy displayed greater gut microbial diversity and an enrichment of Clostridiales, Ruminococcaceae, and Faecalibacterium. This provides further evidence for diet and obesity being linked to breast cancer risk and response to therapy.
Studying immune checkpoints with the gut microbiome
These findings demonstrate significantly improved outcomes in obese cancer patients treated with PD-1 inhibitors. Importantly, obese mice treated with anti-PD-1 showed significantly decreased cell proliferation and a 5.7-fold reduction in tumour volume. Further clinical research is now required into the survival, metastasis and relapse of patients after therapy in response to immune checkpoint therapies to confirm the long-term benefits.
Concerns relating to checkpoint inhibitor drugs include immune-related adverse events. These are a spectrum of side-effects that resemble auto-immune responses and impact almost every organ in the body. However, uncovering biomarkers that can be used to predict a high response rate to immune checkpoint therapies with fewer toxicities would enable improved personalisation of medicine and adverse effects. This study provides evidence for there being possible biomarkers of anti-PD-1 efficacy in the gut microbiome. Therefore, further investigations are required to understand the link between microbiota and responses to immunotherapy, ultimately, enabling the prediction of immune checkpoint therapy efficacy and obesity-mediated impacts.
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