NK CELL RECEPTOR RECOGNITION OF ORAL CANCERS

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DESCRIPTION (Adapted from the Investigator's Abstract): Background: Oral cavity squamous cell carcinomas (OC-SCC) may be susceptible to NK cell surveillance, but little is known about the NK cell receptors and tumor cell ligands involved. Little or nothing is known about the NK receptor surface density, or their relative potency in triggering different effector functions. In contrast to KIR, the LIR- I and LIR-2 recognition epitopes on HLA class I molecules are not known. A unique panel of transformed NK cells mimic normal blood NK cells. Individual NK cells differentially respond to hematopoietic vs. OC-SCC cells, and to primary vs. metastatic autologous OC-SCC cells. OC-SCC cells stimulate NK IFN-gamma secretion via a combination cell surface ligands and IL-18, but not IL-12. Unlike T cells, NK activation by IL-18 does not require IL-12. NK cells are activated by immobilized or Fc receptor-bound anti-receptor mAb in dose-dependent and time-dependent fashions. LIR-I/Ig fusion protein binds selective HLA transfectants, suggesting inhibition by the E63-K66 salt bridge. The experimental plan of this proposal will 1A) search for distinct NK cell response patterns to OC-SCC cells and identify NK receptors and OC-SCC ligands that activate cytotoxicity and IFN-gamma secretion, 1B) characterize how OC-SCC IL-18 and cell surface ligands co-stimulate NK IFN-gamma secretion in primary and metastatic OC-SCC in vivo, 2) quantify four NK receptors by Scatchard analysis, measure the soluble ligand concentration required for NK cytotoxicity and IFN-gamma secretion, and measure the kinetics of activation of NK cytotoxicity and cytokine secretion by cross-linking stimulatory and inhibitory NK receptors, and 3) map how LIR-I/Ig and LIR-2/Ig fusion protein and LIR- 1+ T cells recognize HLA-B*0702 variants to test the hypothesis that all inhibitory NK receptors map to a similar HLA site and may lead to reagents that guide NK attack in vivo. This work combines basic in vitro research and clinical investigation. These studies are a necessary first step to understanding how NK cells recognize and attack OC-SCC in patients. OC-SCC is often directly accessible to injection and topical application of cells, cytokines, and drugs that may focus and augment NK attack. Via knowledge of tumor ligands and NK receptor signaling, better prevention and treatment of OC-SCC may be developed.