RIP Cedric

You may remember stories here and elsewhere about transmissible cancer among tasmanian devils. Devil facial tumour disease (DFTD), as it's called, isn't spread by a virus but rather by allografts of tumour cells of Schwann cell origin that spread from animal to animal by biting. This had raised some interesting questions about the immunology of these tumours. How do they avoid immune rejection? Is it possible to create a preventative vaccine?

One key thought to hold the answer to DFTD that has wreaked havoc on the tasmanian devil community is Cedric, a devil that was thought to be immune to the cancer. But alas, Cedric was recently euthanized after two facial tumours that had been surgically removed had been shown to have spread to the animal's lungs:

In 2007, Menzies researchers injected Cedric and his half brother Clinky with facial cancer cells. Clinky developed the disease, but Cedric showed an immune response and grew no tumors — giving researchers hope that he could help them create a vaccine.

But in late 2008, Cedric developed two small facial tumors after being injected with a different strain of the cancer, which causes grotesque facial growths that eventually grow so large, it becomes impossible for the devils to eat. Current estimates suggest the species could be extinct within 25 years due to the prolific spread of the cancer.

Researchers removed the tumors, and Cedric appeared to be rallying. But X-rays taken two weeks ago showed the cancer had spread to the 5-year-old's lungs, Kreiss said. Tests confirmed the lung tumors were a result of facial tumor disease.

This is a blow to the scientists trying to understand and curtail the spread of DFTD, but hopefully data from Cedric will push forward new strategies to help the devil population.

Tumor Immunology Is A Waste of Time

Ian York recently wrote some interesting stuff about the interesting case of the transmissible tumours that are spreading in Tasmanian devils. The question is how are these tumours transmitted from one host to the next without being rejected by the immune system. He points out some pretty compelling evidence that this is not due to MHC homogeneity amongst the devil population. Therefore, the tumors are persisting despite being MHC mistmatched. In contrast, if you were to transplant normal tissue from one devil to another, it would be rejected by the recipient's immune system. And yet, for these tumors this is not the case. Apparently the same is true of a totally different type of canine transmissible tumor.

We shouldn't find this all that surprising. Tumor cells evolve resistance to almost anything you can throw at them, things that would kill normal cells. Their continued existence demands mechanisms of resistance to death by many diverse types of stimuli. There's only so many ways to kill a cell, so evolved resistance to one stimulus is often cross-protective against many others. The result is that everything down to the most fundamental metabolic processes of the cancer cell are adapted to surviving adversity. In light of this, you would predict T cells would have a hard time killing cancer cells.

Anyhow whatever the mechanism of resistance, all this is enough to convince me that tumor immunologists should give up on trying to make vaccines or other therapeutics that try to cure cancer by targeting "tumor" antigens. If tumors can escape MHC rejection, a natural, more specific and much more robust phenomenon, I find it impossible to believe that effective therapy will ever achieved by artificially stimulating the immune system to attack weak and largely self antigens. I suspect smart immunologists already know this.

UPDATE: In a follow-up post, York points out an important difference between transmitted and spontaneous tumors I hadn't fully considered. That is, the transmitted tumors have a much longer evolutionary history that spans multiple host generations, whereas a spontaneous tumor's evolution follows a blind alley that ends when the host dies. Therefore there has perhaps been greater opportunity for immune evading characteristics to emerge in what may be a more genetically diverse population of transmitted tumors. If this were true, the kinds of non-transmitted tumors we'd like to vaccinate against in humans wouldn't necessarily be as difficult to get the body to reject. At any rate, York remains optimistic re tumor immunology and promises to elaborate so stay tuned...

Systems Tumor Immunology: It's Big Blue Beats Kasparov All Over Again

One innovative approach to cancer therapy involves isolating immune cells (tumor-infiltrating lymphocytes or TILs) from a tumor, and then trying to expand and activate them against tumor antigens in the lab. It can work, but in practice, not an efficient practice. TILs are a mixed bag of cells with all sorts of different personalities, some of which may or may or not be interested in attacking tumor cells. Some, recruited by the ever-devious tumor cells, can even work to supress the activity of the good guys. So sometimes you get a bunch of TILs that work, sometimes not.

A new paper describes a systems biology approach to tackling the complexity of TIL populations with the aim of predicting anti-tumor activity. They profiled the reactivity of a ton of TIL populations, and correlated this inforamtion with a battery of surface markers. They fed the info into some sort of machine learning algorithim, which came up with some pretty clear-cut boolean style predictive rules that a mere organic being (aka tumor immunologist) could never have possibly concieved of with a million years of deductive reasoning and experimental testing.

Check it out:
Rule 1) If the CD8⁺CD28^-CD152^- subpopulation constitutes less than 43% of the entire TIL population AND the CD94+constitutes less than 0.4% of the entire TIL population, then the TIL population is tumor-reactive.

Also, by manipulating the relative proportions of different TIL subpopulations, they could affect reactivity as predicted by their adding machine.

Wicked. Who knew an abacus could do immunology?

See: Predicting and controlling the reactivity of immune cell populations against cancer