Oxygen starvation makes tumours more resistant to antibody treatment

Southampton researchers have discovered how a lack of oxygen can reduce the effectiveness of antibody cancer treatments.

This could show why these treatments do not work for all patients.

Oxygen starvation, or hypoxia, is a key characteristic of the tumour microenvironment. It promotes tumour aggressiveness and how cancer can spread. Despite wide-ranging study over the last three decades, new aspects of hypoxia continue to be found.

The new research, led by the University of Southampton, involved experts and clinicians from across academia and industry. This included scientists from the Centre for Cancer Immunology and consultants from University Hospital Southampton.

Targeted antibodies

The team studied immune cells called monocytes and macrophages (phagocytes). These are important for certain types of antibody treatments, called direct targeting antibodies.

These antibodies include the anti-CD20 antibodies rituximab and obinutuzumab. They are central to many treatments for lymphoma and more recently autoimmune disorders such as rheumatoid arthritis and multiple sclerosis.

However, not all patients respond. These antibodies work, at least in part, by binding the tumour cells and then causing them to be destroyed by monocytes and macrophages in a process called phagocytosis. This process is mediated by activating Fc gamma receptors (FcγRs) and is impaired by one particular FcγR, FcγRIIb.

Effects of hypoxia

In the new study, published in the Journal of Experimental & Clinical Cancer Research, the group comprehensively profiled the effects of hypoxia on monocytes and macrophages.

They demonstrated that hypoxia boosts FcγRIIb, reducing the phagocytic function of macrophages and monocytes, and that this boost is dependent upon two key regulators called HIF-1α and HIF-2α.

The team then went on to show these cells expressing high FcγRIIb are present within tumours in areas of hypoxia and that it impairs the treatment of tumour cells with direct targeting antibodies.

‘Important insight’

The research was jointly led by Professor Mark Cragg, Professor Stephen Beers, Professor Jon Strefford and Dr Stephen Thirdborough from the University of Southampton.

Professor Cragg said: “This work provides an important insight into a previously unrecognised hypoxia-dependent mechanism that can diminish the efficacy of clinically relevant antibody immunotherapies. With this knowledge we can now seek to develop strategies to overcome this process to improve treatments for patients.”

He added: “These findings provide a mechanistic explanation for the modulation of FcγRIIb expression or its blockade as a promising strategy to enhance approved and novel antibody immunotherapies.”

The study was funded by Cancer Research UK.

Image: Centre for Cancer Immunology, University of Southampton.