Genetic Engineering & Biotechnology News

MAY1 2015

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Genetic Engineering & Biotechnology News | | MAY 1, 2015 | 13 perimental medicine, University of Montreal, studies receptor-driven signaling pathways that control NK cell functions. He leads a team of scientists that has been investigating mechanisms for NK cell-mediated killing of abnormal hematopoietic (blood) cells. "We studied the signaling lymphocytic activation molecule (SLAM)-associated pro- tein (SAP) family that consists of a group of intracellular adaptor proteins," says Dr. Veil- lette. "In humans, two members include SAP and Ewing's sarcoma-associated transcript 2 (EAT-2). SAP is an essential component pro- moting NK cell killing of abnormal blood cells, such as is found in leukemia and lym- phoma. Its interaction with SLAM receptors is critical to this process." "Little was known about how EAT-2 functions," he continues. "We wanted to bet- ter understand the cooperation between EAT- 2 and SAP." Using a variety of genetic, biochemical, and imaging strategies, the team identifed the molecular chain of events driving this pathway. They found that EAT-2 and SAP perform very different internal functions us- ing distinct mechanisms of action. "Our studies demonstrated that EAT-2 works by linking SLAM family receptors to phospholipase Cγ, calcium fuxes, and Erk kinase," Dr. Veillette explains. "Unlike SAP, it also accelerates polarization and exocytosis of cytotoxic granules aimed at target cells." According to Dr. Veillette, since these in- tracellular adapter molecules are linked to the cell surface receptor SLAM family, they make attractive therapeutic targets. "For example, Bristol-Myers Squibb is utilizing a SLAM family humanized mono- clonal antibody, elotuzumab, in Phase III clinical studies against multiple myeloma," Dr. Veillette notes. "In May 2014, it was granted Break- through Therapy designation by the FDA. Our future work will focus on better under- standing such receptors and how they are regulated to help identify other potential new treatments for blood cancers." Eluding NK Surveillance Studies demonstrating that the use of cytokines can enhance immune responses against tumors opened up the possibility of using them therapeutically. For example, clinical trials treating advanced melanoma and renal carcinoma with high doses of IL-2 resulted in substantial improvements in a small fraction of patients. Many of the cyto- kines utilized in clinical trials are capable of activating NK cells and may promote antitu- mor activity of these cells. NK-mediated recognition and rejection of tumors is being researched by David H. Raulet, Ph.D., a professor of immunology and pathogenesis at the University of Cali- fornia, Berkeley. He is focused on how regu- lating NK cells can be of beneft in cancer therapeutics. "The effectiveness of NK cells depends on their ability to attack infected or malig- nant cells while maintaining self-tolerance," maintains Dr. Raulet. "Their adaptability to their environment is affected by microenvi- ronmental cues and by the information they receive from host MHC class I molecules. The latter operate via interaction with NK cell inhibitory receptors of the KIR (killer inhibitor receptor) family in humans, and Ly49 molecules in mice (and CD94/NKG2A dimers in both)." Tumorigenesis is often associated with down-modulation of MHC class I mol- ecules on tumor cells, thus priming them for elimination by NK cells. However, often advanced tumor cells are defcient in MHC class I expression but still manage to evade the immune responses by NK cells by un- known mechanisms. A postdoc in Raulet's laboratory, Mi- chele Ardolino, Ph.D., tested whether treat- ment with cytokines known to activate NK cells could enhance therapeutic treatment in tumor-bearing mice via NK cell activation. "We found substantial therapeutic beneft in mice having MHC class I-defcient tu- mors that were treated with a combination of IL-12 and IL-18 or with an IL-2 mutant (H9 "superkine") that functions indepen- dently of the native/normal IL-2 receptor," notes Dr. Ardolino. "These treatments were not effective in mice that had tumors bear- ing MHC class I molecules." Dr. Raulet surmises that the cytokine effcacy was dependent on reversal of the anergic state of the NK cells in the MHC- defcient tumor-bearing mice: "The anergy of the NK cell was associated with impair- ments in early signal transduction of acti- vating receptors in NK cells. 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