Acid discovery raises hopes of improved immunotherapies

Tumours have a more acidic environment (pH 6.5) than normal, healthy tissues (pH 7.2). The new research, led by Dr Ignacio Moraga, from Dundee’s School of Life Sciences, alongside colleagues from Lille University and the University of Cambridge has shown for the first time that this acidity blocks the activities of cytokines. These are proteins critical for mounting potent anti-tumour responses and used in immunotherapy to activate or enhance the body’s response.

Furthermore, the researchers have used protein engineering to design new cytokines that can withstand the acidity found in the tumour environment, leading to more effective anti-tumour responses. There is also no detectable systemic toxicity, something associated with most current cytokine-based therapies.

The paper has been chosen as the cover story for the latest edition of the prestigious journal Science Immunology.

Dr Moraga said, “At its most basic level, our research shows that tumours are very acidic, and this stops the immune response triggered by cytokines from killing them. Tumour treatments have evolved a lot in the last 20 years, but a large proportion of patients still do not respond to immunotherapy.

“High doses of a type of cytokine called IL-2 are used in the clinic to treat cancer and our discovery helps explain why this treatment does not work for most people. IL-2 is a very potent cytokine for driving activation of T cells, which are critical to clear tumours, but it is also very sensitive to the acidic environment.

“We then looked at different approaches for bypassing this limitation and used protein engineering to manipulate the way that cytokines react in the acidic environment. This enabled us to design new cytokines that can activate T cells and promote very potent antitumour responses.”

Cytokines are small soluble proteins that regulate cellular functions essential for normal physiology and the host response to infection and cancer. However, their very complex biology has hindered their translation to the clinic. Most cytokine therapies have resulted in poor efficacy and high toxicity.

Dr Moraga says he and his colleagues are looking forward to furthering the development of these new pH-selective cytokines and expect to enter the first clinical trials within a few years.

He continued, “Having manipulated the sensitivity of IL-2 to boost antitumor responses and decrease toxicity, the aim is to be able to use this mutant to treat human patients with different type of cancers. We are hoping that we will be able to massively improve current therapies and save lives.”