New predictor for immunotherapy resistance in melanoma patients
A new study from Duke Cancer Institute (NC, USA) identified biomarkers predisposing melanoma patients to accelerated cancer growth as a side effect of immunotherapy. This discovery could benefit 10% of all cancer patients where hyper-progression occurs after immunotherapy treatment.
Hyper-progression arises in a small percentage of cancer patients. It is the accelerated growth of cancer after immunotherapy treatment has begun. Previous studies have shown that patients who experience hyper-progression have a median overall survival rate of three months lower than that associated with patients where this does not occur (a survival rate of 4.6 months rather than 7.6 months, respectively). This abnormality can occur in multiple types of cancer, including head and neck, lung and breast cancer. However, this study focused mainly on melanoma.
Immunotherapy drugs, such as checkpoint inhibitors, are a common cancer treatment that works by co-opting the body’s immune system to fight off cancer. These checkpoint inhibitors signal to T-cells to kill the cancer cells as they have blocked checkpoint proteins from binding to their receptors on the cancer cells. This in turn means that the ‘off’ signal is not sent to the T-cells for the cancerous tumor. This cancer therapy is successful in a large portion of patients. However, hyper-progression can occur when certain protein complexes are present in tumors, leading to the spread of cancer in the patient.
“There is a continuum between resistance to immunotherapy and the development of a hyper-progressive state,” explained senior author Brent Hanks, associate professor in the Department of Medicine at Duke University School of Medicine.
This study sought to identify what could be causing the resistance to immunotherapy in some cancer patients. Both human and mouse tissues were analyzed, utilizing the ELISA (enzyme-linked immunosorbent assay) and western blot techniques, to detect and measure the concentrations of the NLRP3 inflammasome in the melanoma tumor samples.
Inflammasomes are naturally part of the body’s immune system. Their role is to identify when a foreign body is present. However, the researchers found that in certain cases the NLRP3 inflammasome in tumors responds to activated T-cell responses, triggering a chain of events that leads T-cells to resist the checkpoint inhibitor drugs. This shields the cancer and allows it to proliferate and metastasize throughout the body, causing hyper-progression.
Once the research team understood the role of NLRP3 inflammasome in hyper-progression, they turned their attention to identifying which patients would be most vulnerable to it. The researchers used western blotting to measure the concentrations of the molecules associated with inflammasome interactions. They elucidated that treatment with Anti-PD-1 immunotherapy increased the activation of signaling pathways seen in the lungs (the Lung epithelial HSP70-TLR4) via immunologic pressure and accelerated disease progression in the presence of Nlrp3 amplification. They found that the patients with high baseline levels of the molecules associated with the inflammasome interactions had a greater association with hyper-progression and, therefore, a lower survival rate.
Brent commented on the impact of this research:
“While hyper-progression occurs in a small percentage of cancer patients receiving checkpoint inhibitors, identifying the likelihood of this phenomenon has the potential to alter the clinical approach and avoid this complication.”
The research team is working with Duke colleagues on a clinical trial investigating a therapy that inhibits the activity of NLR3 inflammasomes in patients who have become resistant to immunotherapy using checkpoint inhibitor drugs.
Sources
Thevianthiran B, Yarla N, Haykal T et al. Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti–PD-1 immunotherapy. Sci Trans Med. 14(672), doi: 10.1126/scitranslmed.abq7019 (2022)
Duke Health press release: www.corporate.dukehealth.org/news/biomarker-predicts-resistance-immunotherapies-melanoma
