Melanoma and metastasis

Key Points

National report - Downregulation of interferon signaling appears to be a dominant mechanism by which melanoma is able to escape control by the immune system and thrive.

Previous research had implicated loss of immune control as a factor in metastasis for several forms of cancer, but no one was quite sure of the mechanism. Now Peter P. Lee, M.D., and colleagues at Stanford University, Stanford, Calif., have zeroed in on interferon signaling as the explanation for the emergence of melanoma.

Initially, the discovery might help in the selection of patients who are most and least likely to respond to existing interferon therapy, and avoid the often brutal side effects if the treatment is not likely to work. It also might yield other possible targets for the development of interventions to correct dysfunctional interferon signaling pathways.

Often 50 to 100 disparate genes are found to be up or downregulated; they are a laundry list of genes, Dr. Lee explains. Many of those changes are not related to each other or they are generic to a broad process, such as inflammation. Further digging is required to understand just what, if anything, is significant to the disease under investigation, he says.

Few genes implicated

Dr. Lee says he was "absolutely surprised and delighted" to see that only 25 genes differed between the two groups that researchers screened, and that 17 of those were interferon-stimulated genes.

"That is an extremely tight clustering of these genes around interferon signaling. When you take into account the entire pathway, the p value is 10-27, which is phenomenal," he says.

That same pattern of gene expression repeated itself regardless of whether investigators looked at CD8 T cells, CD4 T cells or B cells. The sole exception was NK cells, in which gene expression didn't budge.

"We were very surprised that NK cells did not change at all. NK cells have been implicated to be perturbed in head and neck and other types of cancers, so we were fully expecting NK cells to come up as well," Dr. Lee says.

Additional work with lymphocytes from patients with melanoma showed lower expression of key activation markers for interferon, confirming that they did not respond normally when exposed to the molecule. However, higher doses and longer exposure to interferon did begin to restore normal response.

The gene expression only came up with type 1 interferon, Dr. Lee tells Dermatology Times.

"It just so happens that interferon alpha is a treatment that works with melanoma, so it fits together really nicely," he says.

Most of the affected genes "were downregulated two to fourfold in the blood; these are not sledgehammer-type changes. So I wouldn't expect that to change dramatically in earlier stages of melanoma," he says.

His lab has begun trying to confirm that hypothesis.

Dr. Lee says what is more likely to change in earlier stages of melanoma is the percentage of T cells in the blood that experience these changes.

"But if we had an opportunity to look at T cells that directly infiltrate the tumor or in the draining lymph nodes, then we might see a difference in gene expression itself."

His lab is beginning to look at T cells from patients with breast cancer to see if he can see the same phenomena. And if that proves to be the case, then next on the list may be colon and prostate cancers.

He expects that "interferon signaling is going to be an important part of response to other types of cancer."

He adds, "We are trying to understand the mechanisms better; particularly the correlation with clinical outcomes, and working on alternative strategies to overcome this defect.

"In some ways we came to this through the back door," Dr. Lee says.

The fact that more than a third of melanoma patients respond to interferon treatment while others do not had suggested to him that interferon signaling might play an important role.

"If we can confirm that the mechanism by which interferon alpha leads to clinical benefit is by restoring T cell function by overcoming the interferon signaling defect, then we can potentially find other ways to correct the defect that might be more effective, or have fewer side effects," he says.

For more information:
Critchley-Thorne RJ, Yan N, Nacu S, Weber J, Holmes SP, Lee PP. Down-Regulation of the Interferon Signaling Pathway in T Lymphocytes from Patients with Metastatic Melanoma. PLoS Med. 2007;4(5):e176 [Epub ahead of print]