Protein Chimera Activates Antitumor Immunity in Mouse Model

Cancer researchers have synthesized a chimeric protein comprising the large stress protein or chaperone Grp170 and a fragment of the bacterial protein flagellin that blocked tumor growth and metastasis by mobilizing or restoring antitumor immunity.

Molecular chaperones are proteins and protein complexes that bind to misfolded or unfolded polypeptide chains and affect the subsequent folding processes of these chains. All proteins are created at the ribosome as straight chains of amino acids, but must be folded into a precise, three-dimensional conformation in order to perform their specific functions. The misfolded or unfolded polypeptide chains to which chaperones bind are said to be "non-native," meaning that they are not folded into their functional conformation. Chaperones are found in all types of cells and cellular compartments, and have a wide range of binding specificities and functional roles. The chaperone Grp170 is being evaluated for its potential in cancer chemotherapy due findings that indicated that this molecule prompted the immune system to recognize cancer antigens.

Flagellin is a 30,000 to 60,000 Dalton globular protein that arranges itself into a hollow cylinder to form the filament in bacterial flagellum. This protein is the principal constituent of bacterial flagellum and is present in large amounts on nearly all flagellated bacteria. Mammals often have acquired immune responses (T-cell and antibody responses) to this flagellar antigen.

Investigators at Virginia Commonwealth University (Richmond, USA) strategically incorporated a pathogen flagellin-derived, NF-kappaB-stimulating "danger signal" fragment into the large chaperone Grp170 protein that previously had shown the ability to facilitate antigen cross-presentation.

They reported in the January 18, 2013, online edition of the journal Cancer Research that this engineered chimeric molecule, which they called Flagrp170, was capable of transporting tumor antigens and concurrently inducing functional activation of dendritic cells. Injection of nonreplicating adenoviruses expressing the gene for Flagrp170 directly into tumors induced a superior antitumor response against B16 melanoma and its distant lung metastasis compared to unmodified Grp170 and flagellin. The enhanced tumor destruction was accompanied with significantly increased tumor infiltration by CD8+ cells as well as elevation of interferon-gamma and interleukin-12 levels in the tumor sites. The therapeutic efficacy of Flagrp170 and its immune stimulating activity were also confirmed in mouse prostate cancer and colon carcinoma.

"Successfully promoting antitumor immunity will help eradicate tumor cells, control cancer progression, and help prevent tumor relapse," said senior author Dr. Xiang-Yang Wang, associate professor of human and molecular genetics at Virginia Commonwealth University. "This immunotherapy has the potential to be used alone or in combination with conventional cancer treatments to develop and establish immune protection against cancer and its metastases."

"Overcoming cancer's ability to suppress the body's natural immune responses and restore or develop immunity for tumor eradication is the goal of cancer immunotherapy," said Dr. Wang. "More experiments are needed, but we are hoping Flagrp-170 may one day be used in formulating more effective therapeutic cancer vaccines."

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