Wiping out Mr. Hyde - Fighting macrophages that foster immune escape and tumour growth

Macrophages in the human body have two faces. They are large, specialized immune cells that normally act as the first line of defence in protecting the body from infection.  As soon as they recognize invaders – in this case cancer cells – as “foreign,” they engulf and destroy them. They also secrete chemicals which call in an attack on the invaders from the immune system.

However, if these defenders come under the influence of malignant cancer cells, they then turn into a sort of molecular “Mr. Hyde.”

Macrophages are lured in by tumours, where they are reprogrammed by the chemical microenvironment to become what are known as tumour-associated macrophages (TAMs) that actively foster tumour growth.

Chemical messengers called cytokines, secreted by the TAMs under the oxygen-deficient conditions within the tumour, promote the formation of new blood vessels that supply the tumour. The TAMs also play a role in the suppression of killer T cells, which normally attack cancerous cells. If that wasn’t enough, in an especially malicious twist, proteins that are produced by TAMs help to shield the tumour from the effects of chemo- and radiation therapy. They also contribute to the spread of metastases throughout the body.

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Colorectal cancer tissue slide showing the Invasive Margin (IM) with a rim of macrophages between the normal and tumoural tissue. Macrophages are stained brown. The invasive margin is the border between the normal colon mucosa and the tumoural area.

A team headed by Carola Ries, Senior Principal Scientist at the Roche Innovation Center in Penzberg, Germany, is involved in research and early development of investigating the role of TAMs in the tumour environment, as well as analysing how TAMs that have infiltrated the tumour can be wiped out.

A specific protein called colony stimulating factor 1 or CSF1, which is overproduced in many types of solid tumours, binds to the CSF1 receptor (CSF1R) on the surface of macrophages. This binding attracts the macrophages to the tumour and boosts their proliferation within the tumour environment. “Our goal is to find ways to stop that interaction and hence the generation of TAMs,” says Carola. “We need to ensure that the CSF1 receptor is no longer activated in order to turn off and ultimately kill these misdirected macrophages.”

“Cancer has found many ways to evade established therapies such as chemotherapy,” says Dominik Rüttinger, Clinical Leader for Translational Medicine at the Roche Innovation Centre in Penzberg. “While initial preclinical results have been promising, we are not so presumptuous as to assume that tumours would disappear from the depletion of TAMs alone. We believe that approaches that target TAMs could – and ideally should – be combined with others to achieve clinically optimal results,” says Dominik.

The potential of TAM inhibition could be high. It could potentially help overcome resistance to chemo- and radiation therapy, one of the biggest problems in cancer management. TAMs, taken into molecular custody by cancer cells, secrete proteins such as MMP9 or cathepsins that can shield tumours from the toxic therapies. By blocking that process, the tumour could be made vulnerable to them once again.

Another potential approach to TAM inhibition would involve blocking the CSF1 receptor in addition to blocking the receptors responsible for the growth of new blood vessels.  TAMs usually promote this process (called angiogenesis), so blocking it could help normalize the tumour’s nutrient supply chain.

A third potential approach could lie in reversing the multiple mechanisms that tumour cells use to evade an immune attack at the same time. For example, so-called immune checkpoint inhibitors expressed on the surface of immune cells are necessary in healthy individuals to keep those cells in check, and hence guard against an over-reactive immune system, or autoimmunity. Some cancers, however, use those same checkpoint inhibitors to hide themselves from the immune system. In these patients the blocked immune response has to be turned on again by targeting those checkpoint inhibitors. Simultaneous CSF1 receptor blockade may enhance the effect of the re-activated immune response.

Research is progressing fast on the role of TAMs in the tumour microenvironment, so what failed in Robert Louis Stevenson’s famous novel could succeed in oncology: the team hopes to potentially gain control over Mr. Hyde and thus take a further step towards the development of more effective cancer therapies.