Apr. 25, 2012 Johns Hopkins and Yale scientists have found that melanoma cells use a cloaking protein to hide from immune cells poised to attack the cancer. Nearly 40 percent of their sampling of melanoma tissues contained the B7-H1 protein, also called PD-L1, and scientists say it could be used as a target for new therapies.
For the study, described in the March 28 issue of Science Translational Medicine, the research team analyzed 150 samples of benign melanocytic lesions, and primary and metastatic melanomas, looking for expression of B7-H1 above a threshold of five percent. Of the samples, collected from patients at Johns Hopkins, 57 (38 percent) were positive for the B7-H1 cloaking protein.
Previous research by Yale scientist and B7-H1 discoverer Leiping Chen, Ph.D., formerly of Johns Hopkins, established that some melanoma cells express B7-H1, which renders the cells invisible to T-cells. These t-cells release interferon gamma, a potent signal to trigger cancer cell-killing. But it turns out that interferon gamma also prompts melanoma cells to make more B7-H1, further cloaking the melanoma cells from the immune system.
"It's a self-defeating process that may explain why immune cells penetrating melanomas can't kill them," says Janis Taube, M.D., assistant professor of dermatology and pathology at Johns Hopkins. "The immune cells are standing ready to attack, but the melanoma cells are holding them at bay by using the B7-H1 protein," she adds.
Notably, in the current research, the approximately 40 percent of patients with metastatic melanomas harboring B7-H1 expression had moderately better survival than those without, probably, the researchers say, because B7-H1 expression indicates that the patient's immune system is beginning to respond to the tumor. "Since T-cells trigger melanoma cells to produce B7-H1, we believe that finding significant expression levels of the protein is an indicator that the immune system has been activated," says Taube.
Nearly half of the patients with metastatic melanoma had received some form of immunotherapy aimed at boosting the immune system's ability to fight cancer. Taube says this may have tipped the balance in favor of the immune system despite the cloaking effect.
"When melanoma cells express B7-H1 and immune cells arrive at the site, an immunotherapy that blocks B7-H1 expression can turn off this cloaking protein so that immune cells can deliver a fatal blow," adds Taube.
Because most normal tissues generally do not express B7-H1, therapies that block the protein could be specific to the melanoma cells and expression of the protein could be used as a biomarker for patients who may respond to the therapies, the researchers say.
Taube also says that the results could apply to other types of B7-H1-expressing tumors.
In addition to Taube and Chen, other scientists contributing to the research included Robert A. Anders, Geoffrey D. Young, Haiying Xu, Rajni Sharma, Tracee L. McMiller, Shuming Chen, Alison P. Klein, Drew M. Pardoll, and Suzanne L. Topalian from Johns Hopkins.
The research was funded by the National Cancer Institute (grants CA016359, CA97085 and CA85721), the National Institutes of Health (grants R01DK080736 and R01DK081417), the Melanoma Research Alliance, the Barney Family Foundation, the Michael Rolfe Foundation for Pancreatic Cancer Research, and the Dermatology Foundation.
Topalian is a consultant to Bristol-Myers Squibb and Topalian, Taube, Anders and Xu receive research support from Bristol-Myers Squibb. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.
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- J. M. Taube, R. A. Anders, G. D. Young, H. Xu, R. Sharma, T. L. McMiller, S. Chen, A. P. Klein, D. M. Pardoll, S. L. Topalian, L. Chen. Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape. Science Translational Medicine, 2012; 4 (127): 127ra37 DOI: 10.1126/scitranslmed.3003689
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