APRIL 2017 – Tumour ischaemia by interferon-γ resembles physiological blood vessel regression

Abstract

The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models. Although IFNγ can impede tumour growth by acting directly on cancer cells, it must also act on the tumour stroma for effective rejection of large, established tumours. However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNγ induction and an IFNγ–GFP fusion protein in large, vascularized tumours growing in mice that express the IFNγ receptor exclusively in defined cell types. Responsiveness to IFNγ by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNγ-induced tumour regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFNγ-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNγ-mediated, pregnancy-induced remodelling of uterine arteries. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.

Interview

For their work on the effects of the chemical signal molecule interferon gamma in the development of cancer, the paper by Thomas Kammertoens and Thomas Blankenstein from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association was chosen as Paper of the Month in April. Their work provides pointers for improved T-cell therapy against solid cancer tumors. We asked them about their research and the project.

What are you researching? What does your research focus on? What motivated you to perform this research?

We are interested in the interaction between different cancers and the immune system. In particular, we want to understand how certain immune cells (T-cells) can successfully attack and destroy a solid tumor, and above all which signaling molecules of the immunsystem need to act and how they work, and the order in which certain cells (blood vessel cells, cancer cells, etc.) are destroyed. Above all, we are curious about how the immune system and tumors interact with each other under normal or therapeutic conditions, and of course we would like to answer questions which not only we consider relevant, but which are of general interest, and which could lead to a better understanding of the illness and the therapy. What motivates me are curiosity and the conviction that it will answer relevant questions.

What is the essence/core message of your publication and how does your study differ from the work of other scientists in this field?

We were able to show that a certain signaling molecule (interferon gamma, IFNg), which is mainly formed by T-cells, has a very strong and direct effect on activated blood vessels in the tumor. The tumor's blood vessels recede and the tissue is no longer supplied with oxygen and nutrients, causing it to die. Furthermore, our findings also suggest that other physiological processes in which activated blood vessels play a role, such as the healing of wounds, and perhaps even tissue regeneration after a heart attack or a stroke, may also be influenced negatively by the chemical messenger IFNg.

Our study is based on a unique but complicated genetic model which allows the effect on individual cell types in the tumor to be studied. Furthermore, in collaboration with Hans Schreiber, we also utilized a model which allows the tissue changes after the release of IFNg to be studied at the microscopic level in living tumor tissue with a great degree of precision.

Which collaborations resulted in the publication? Who were the major contributors to the work?

In Berlin, we worked closely with researchers of the Max Delbrück Center, the Charité, and the BIH. Deserving of particular mention are the angiogenesis specialist Holger Gerhard and the bioinformatics expert Dieter Beule. Furthermore, we also worked with colleagues from England and the USA. Deserving of particular mention here is Hans Schreiber from the University of Chicago, who is an Einstein Visiting Fellow at our institute.

What are the next steps planned for the project and what are the possible implications of your findings for patients?

Our study suggests that two important immune messengers work together synergistically (TNF and IFNg). This is certainly an interesting aspect to investigate.

Unfortunately, there is no good prognostic indicator at the moment which allows for the early prediction of success when T-cell therapy is used to treat solid tumors. Our data suggests that IFNg measurements may be a good predictor (biomarker) for T-cell therapy. We will definitely be carrying out a number of experiments in this area. Whether, as previously mentioned, IFNg interferes with healing processes during tissue healing (e.g. heart attacks), and whether this is a relevant question at all, is a matter that other scientists working on these issues will need to decide.