Immune System's Initial Response to Cancer Studied

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, said Dr. Kraj, who hopes better understanding the process 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 winnowing 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 eventually develop a memory for thousands of antigens they encounter: everything from pollen to viruses. “Generally, the mouse has a wide, abundant repertoire of T cell receptors,” said Dr. Kraj. “If you take 10,000 T cells, there is a good chance each cell’s is different.”

In the 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 said. “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, said 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,” said Dr. Kraj.

This is where T cells decide whether to attack or ignore antigens. Unfortunately, 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,” said Dr. Kraj. “It’s like natural selection: the fittest survive. 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 thin out the crowd and watch specific cells. “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.”

He hopes the 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,” said Dr. Kraj. “Also, the same mechanisms that make the immune system recognize cancer may also work in recognizing your own tissue.”

--Toni Baker

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