Cancer's defence mechanism probed

Behind the Headlines

Friday November 5 2010

The study looked at cancer cell behaviour, not a vaccine

We are a step closer to a cancer vaccine that “could revolutionise treatment”, The Daily Telegraph has reported. The newspaper said that scientists “have discovered how tumour cells protect themselves from the body's natural defences”.

This news is based on early research that looked at why some cancer may be resistant to the body’s immune response. The researchers found that stromal cells, which form the connective tissue of tumours, may act to suppress the immune system’s response to tumours. In the study, researchers took genetically modified mice and selectively knocked out some types of stromal cells, which then slowed the growth of the tumours. A pair of proteins was also implicated in this process, with the positive effects of knocking out stromal cells being reduced when these proteins were neutralised.

This aim of research had not been to develop a vaccine against cancer; rather it was to further the understanding of how tumours can be resistant to the immune response. This basic research has increased our understanding of cell-to-cell interactions in tumours and has highlighted important areas for future drug research to focus on.

 

Where did the story come from?

The study was carried out by researchers from the University of Cambridge and was funded by the Wellcome Trust and the National Institutes for Health Research. The study was published in the peer-reviewed journal, Science.

This research was covered well by BBC News. The Daily Telegraph and the Daily Express reported that the researchers had demonstrated that a protein called FAP (fibroblast activation protein-α) was responsible for suppressing the body’s immune response against tumours. The researchers have not implicated this protein in their mouse research, rather they have developed a technique to knock out stromal cells. This is a specific type of cell found in limited quantities in tumours that also has the ability to produce the FAP protein. How these cells suppress the immune response has not been fully revealed by this research.

 

What kind of research was this?

This laboratory-based research looked at stromal cells, which make up the connective tissue of tumours. The researchers were interested in finding out why some anti-cancer vaccines fail, and how stromal cells may be involved in suppressing the immune response in the tumour environment. In particular, the researchers were interested in stromal cells that produce the protein fibroblast activation protein-α (FAP). Such cells make up approximately 2% of all of the cells in tumours.

The researchers used mice that had been genetically engineered in a way so cells that made FAP could be removed. They could then look at the response of the tumour when these cells were removed.

 

What did the research involve?

The researchers made two types of genetically modified mice. In one type, the cells containing FAP would produce green fluorescent light and in the other type of mouse, the cells producing FAP also produced a protein called the diphtheria toxin receptor (DTR). These DTR-producing cells could be selectively destroyed if the mice were exposed to the diphtheria toxin.

The researchers took the mice with the green fluorescent cells and injected them with tumour cells to further understand what other proteins were expressed in the FAP-positive stromal cells using fluorescent probes targeted towards specific proteins.

To see whether the FAP-positive stromal cells contributed to tumours’ resistance to vaccination, the mice were either vaccinated then injected with lung cancer cells to induce a tumour, or given the vaccine when the tumour was at a stage when it could be detected by touch. The researchers assessed the effectiveness of the vaccine with or without the FAP cells present in the tumour.

The researchers also compared tumours taken from the normal mice and the DTR mice that had been treated with diphtheria toxin.

 

What were the basic results?

By looking at the proteins produced by the FAP-positive cells, the researchers determined that some of the cells possessed some of the same markers as ‘mesenchymal stem cells’ (which can mature into other types of cells such as bone and cartilage cells) and ‘fibrocytes’ (which are found in connective tissue).

Vaccinated mice showed less tumour growth than mice that were not given the vaccine prior to injection with tumour cells. If the vaccine was given after the tumour had formed, it did not slow subsequent growth of the tumour. However, if FAP-positive cells were knocked out then tumour growth was fully suppressed. In animals that had not received any vaccination, removal of FAP-positive cells slowed the growth of tumours.

The researchers then looked at markers of an immune response generated by the presence of a tumour. They found that the loss of FAP-positive stromal cells arrested the growth of tumours that had induced an immune response but not of tumours that had not.

The researchers then looked at the tumour tissue. They found that growth arrest was associated with a 60% decrease in the number of viable cells (both cancer and stromal cells) per gram of tumour. The researchers found that the tumour cells contained the proteins TNFα and IFNγ, two inflammatory proteins that may be involved in causing cell death. If mice were given antibodies that neutralised the effects of these proteins, the depletion of FAP positive cells had a reduced effect upon the arrest of tumour growth.

 

How did the researchers interpret the results?

The researchers said that FAP-expressing cells play a functional role in the “immune-suppressive component of the tumour microenvironment”.

They suggested that one of the normal roles that FAP-positive stromal cells may have is to protect tissue from immune responses, however in the case of tumours this may be “catastrophically inappropriate”. They suggest that interfering with the mechanisms underlying the suppression of the immune response by the stromal cells may complement current cancer immunotherapy.

 

Conclusion

This was well conducted basic research that furthers the understanding of how cells interact in a tumour. Vaccine therapies are already used in the prevention of some cancers such as cervical cancer, but this study highlights one mechanism that may currently prevent the effectiveness in immunotherapy for developed tumours.

In the long-term it may lead to new drug targets being investigated and promote vaccine-based therapies as an option in cancer treatment. However, while this research in genetically modified mice provides a good starting point for future studies, at the moment it has limited immediate direct relevance to human therapies.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Cancer vaccine allows body to kill tumours. The Daily Telegraph, November 5 2010

Cell find may aid cancer vaccines. BBC News, November 5 2010

Key breakthrough brings jab to beat cancer a step closer. Daily Express, November 5 2010

Links to the science

Kraman M, Bambrough PJ, Arnold JN et al. Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein AlphaScience, 5 November 2010: Vol. 330. no. 6005, pp. 827 - 830

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