Why the Immune System Ignores Cancer

Kat -   Also in the news this week, scientists have made a breakthrough that could provide a new way to combat cancer and Cambridge University researcher Professor Doug Fearon has discovered that when cancers develop, they attract stem cells from elsewhere in the body.  These stem cells, which carry a marker called FAP, seem to produce immune suppressing chemicals that prevent the immune system from attacking the tumour.  But remove these cells and the cancer then becomes vulnerable to immune attack...

Doug -   The problem that we wanted to solve was how did the tumour microenvironment prevent killing of tumour cells, cancer cells, by immune cells?  We approached the problem by asking if there were cells in the tumour microenvironment that you actually would find in other places where we thought immune suppression would be physiologically reasonable like healing wounds or even the uterus and placenta.  And it was a cell type that you could find in healing wounds, and in placenta that had first been described in 1990 by Lloyd Old, present in essentially all human adenocarcinomas.  This cell could be recognised by its expression of a membrane protein which we'll call FAP, which is an acronym for Fibroblast Activation Protein.  So using this as a membrane protein to identify a specific cell, we devised a genetically modified mouse strategy in which we could kill FAP expressing cells conditionally after tumours had formed in the mice, to see what would the effect be on immune killing the tumour.

Chris -   So your theory is that something is stopping the immune system attacking a cancer and that these cells that appear to be recruited from around an animal's body - these ones that are FAP positive, they make these fibroblast activation protein - they're the cells you believe that are suppressing the immune system.  So if you get rid of them, the immune system should be able to attack the tumour.

Doug -   Yes.  That was a hypothesis we wanted to test was, if we were to kill that cell and only that cell in the tumour, could the immune system then control tumour growth?  The outcome of the experiment was that when we did deplete the tumour microenvironment of these cells, the immune system did indeed kill the tumour or reduce the number of viable cells in the tumour within 48 hours.

Chris -   How did you get rid of the FAP positive cells in the cancers in the mice?

Doug -   That's been a very nice development over the last few years, where you can target the expression of human diphtheria toxin receptor, to particular cell types genetically in modified mice, because mice don't have a diphtheria toxin receptor.  And if you give diphtheria toxin, the receptor internalises that toxin, a toxin turns off protein synthesis in the cell, and the cell dies within 24 hours.  So the experiment is based on the fact we made mice in which the diphtheria toxin receptor would be expressed only in FAP positive stromal cells and nowhere else.

Chris -   So you put tumours into a mouse, they get these FAP positive cells in there, you delete those cells using this diphtheria toxin technique, and the tumours then regressed?

Doug -   They did in 48 hours - either didn't grow or actually got slightly smaller.  In addition, the number of viable cells that we found in the tumour was decreased by about a half to 2/3.  So, there was, overall, maybe about 80% fewer viable cells in that tumour than in a controlled tumour, just 48 hours after the addition of diphtheria toxin.

Chris -   Is this exclusive to the experiments you've done or would you find the same population of cells in any kind of cancer, and therefore, the technique would generalise to other tumour types?

Doug -   Well, as I said, this cell was discovered by Lloyd Old in 1990, published in a PNAS paper, showed that it was present in essentially all human adenocarcinomas.  So, if the FAP expressing cells in humans have the same function as they appear to in mice, then potentially, if we could get at that cell in humans, most human adenocarcinomas might become more susceptible to immune control.

Chris -   And do you know why those cells stop the immune system attacking the tumour?

Doug -   The only insight we have now, which is pretty limited, is that we know we can block the tumour killing by giving neutralising antibodies tumour necrosis factor and interferon gamma, two cytokines made by immune cells, interferon gamma, particularly by T-cells.  So we presume somehow that FAP expressing cells are inhibiting the tissue response to these two cytokines.

Chris -   So the next step will presumably be to ask, can you ubiquitously get rid of FAP in the long term and see what happens to these animals?  Will they stay healthy?

Doug -   These cells are found in bone marrow, bone, adipose tissues, skeletal muscle, retina, olfactory epithelium of the nose, tongue - so a variety of different normal tissue sites, which has not been appreciated before, and it's looking like they have some important functions in these tissues, but we're still working on that.  So I don't think it'll be a therapeutic option to simply kill these cells all over the body.  I think somehow, we have to interfere with their function selectively in a tumour, so we need to be a little more sophisticated.  We need to know and understand what these cells do.  Do they make a protein that we could inhibit in some way?  Can we inhibit how they accumulate in the tumour?  Those are the approaches we have to develop.  We can't have a blunderbuss approach of killing them off in the entire individual.

Chris -   So is that the next step then, to try and work out how you can target just those cells in just the tumour environment and not have ubiquitous killing throughout the body because there probably will be consequences.

Doug -   So, what we are doing is that we've looked at the genes that are being expressed in FAP expressing cells in adipose tissues, skeletal muscle, bone and tumour.  And then we go to the tumour and say, what are the genes uniquely expressed in the tumour FAP cells?  Might they be related to immune suppression?  Might there be targets that we could have some therapy directed at and we're right in the middle of that.