A lack of oxygen (hypoxia) makes tumours more resistant to antibody treatments, according to a new study by scientists at the Centre for Cancer Immunology.
The researchers believe this could indicate why antibody treatments do not work for all patients.
Hypoxia is a key characteristic of the tumor microenvironment, promoting tumor aggressiveness and how cancer can spread. Despite extensive study over the last three decades, new aspects of hypoxia continue to be found.
Funded by Cancer Research UK and working with researchers and clinicians across the University’s Cancer Sciences department, other academic institutions and colleagues in industry, the team studied immune cells called monocytes and macrophages (phagocytes), which are important for certain types of antibody treatments, called direct targeting antibodies.
These antibodies include the anti-CD20 antibodies rituximab and obinutuzumab, which have become the mainstay of 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 tumor cells and then causing them to be physically engulfed and destroyed by monocytes and macrophages in a process called phagocytosis. This process is mediated by activating Fc gamma receptors (FcγRs) and is impaired by the sole inhibitory FcγR, FcγRIIb (Nimmerjahn and Ravetch, 2008).
In the new study, published in the Journal of Experimental & Clinical Cancer Research, the group used microarrays, RNA sequencing, network analysis and ATAC-seq, in combination with unique in vitro and in vivo models, to comprehensively profile 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 human and murine tumors in areas of hypoxia and that it impairs deletion of tumor cells with direct targeting antibodies.
Professor Mark Cragg who led the work jointly with Professor Stephen Beers, Professor Jon Strefford and Dr Stephen Thirdborough, said: “This work provides an important insight into a previously unrecognized 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.