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A mouse model enabling studies of the immune system's initial response to cancer has been developed by a Medical College of Georgia researcher.
"The immune system may do two things: It may destroy your cancer, hopefully, and it may not destroy it," says Dr. Piotr Kraj, immunologist. "It's not known how the decision is made what to attack and what not to."
First glance is the best time to eliminate a cancer, says Dr. Kraj who hopes better understanding of how that does – and doesn't – happen will lead to new treatments utilizing the body's natural defenses. Funding from the Georgia Cancer Coalition's program for young investigators helped him develop the model. He recently received a five-year, $1.1 million grant from the National Cancer Institute to use the model to study prostate cancer and melanoma.
The work started with whittling the vast immune response to an examinable number of different T cells, which orchestrate the immune response, and expressing a known antigen in tumor cells that provokes the response.
The body has millions of T cells produced by the thymus, that start life naïve, then develop a memory for thousands of antigens they encounter: everything from pollen to viruses to the body's own proteins and peptides. "Generally the mouse has a wide, abundant repertoire of T cell receptors," says Dr. Kraj. "If you take 10,000 T cells, there is a good chance each cell's is different.
"We wanted a system where we could look at a population of antigen-specific cells. The way we could do that is by making a transgenic mouse. The specificity of the T cells is biased to recognize one peptide and we know what that peptide is. We have a prostate cancer cell line that expresses this peptide. We can now move to the experiments where we can inject those mice with prostate tumor cells and see what happens," Dr. Kraj says. "We already are doing that with melanoma cells."
The usual first place antigens and T cells meet is in the draining lymph nodes, which also are part of the immune system. When cancer spreads, it typically moves through this natural drainage system. If all goes well, long before that happens, the body has seen and eliminated the cancer, says Dr. Kraj. Very early in the disease process, immune cells called dendritic cells take cancer antigens – and all antigens – to the draining lymph nodes and present them to the T cells. "It's like a meeting place for all cells," says Dr. Kraj.
In this meeting place, T cells decide whether to attack or ignore antigens. Unfortunately and amazingly, wily cancer cells can go into defense mode and avoid producing proteins recognizable to the immune system. "Tumor cells that survive and make the tumor are those that are least recognized by the immune system," says Dr. Kraj. "It's like natural selection: the fittest survive. Basically, the immune system kills all of what it can recognize and we are left with those cells that are most resistant to the immune system. Now the question is, is the tumor shaping the immune system as well" by also neutralizing cells most likely to respond to cancer?
Dr. Kraj's model enables him to study this important give and take by knowing which cells to watch and thinning out the cell crowd enough to do it. "I am going to express this antigen in a tumor cell and look back at what's happening to those particular cells in this particular mouse. It's not like all the immune cells will get anergic (unable to generate an immune response) or will get deleted or get activated. It's just those particular cells specific for this particular antigen that should be affected."
He hopes the up-close studies will shed light as well on why the immune system sometimes turns on the body, such as in autoimmune disease like arthritis and type 1 diabetes. "Probably the same mechanisms that are responsible for tolerance to cancer are responsible for tolerance to self tissues," says Dr. Kraj. "Also, the same mechanisms that make the immune system recognize cancer may also work in recognizing your own tissue."
Dr. Kraj joined the MCG faculty in March 2003 after working as a postdoctoral fellow in the laboratory of Dr. Leszek Ignatowicz, also an immunologist in the MCG Institute of Molecular Medicine and Genetics.