Mark Smyth

..To further elucidate its role in breast cancer progression, CXCL12 and its antagonist CXCL12(P2G) were overexpressed in the syngeneic 4T1.2 mouse model of breast carcinoma...

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..These results indicate that a rational combination of Ab-based therapy that causes tumor cell apoptosis and a cytokine that promotes T cell memory is a useful new strategy for cancer immunotherapy...

..Our data illustrate at least one mechanism by which Treg can suppress NK cell antitumor activity and highlight the effectiveness of combining Treg inhibition with subsequent NK cell activation to promote strong innate antitumor immunity...

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..This review will discuss the functional importance of NK cell cytotoxicity and the receptor/ligand interactions that control these processes...

..Overall, the data suggest that NK cell antitumor function can be enhanced greatly by strategies that are designed to expand and differentiate NK cells via DC activation of NKT cells...

..These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation...

..These data further support the use of IL-21 in adjuvant settings where strong T cell-mediated immune responses to tumors can be generated...

..These developmental changes suggested that IL-21 functions to induce the terminal differentiation of mouse NK cells, resulting in heightened NK cell-mediated cytotoxicity and immune surveillance...

..TRAIL gene-targeted mice were also more sensitive to the chemical carcinogen methylcholanthrene. These results substantiated TRAIL as an important natural effector molecule used in the host defense against transformed cells...

..A significant incidence of late onset adenocarcinoma observed in both IFN-gamma- and pfp-deficient mice indicated that some epithelial tissues were also subject to immunosurveillance...

..Our study has illustrated the practical advantage of engineering a T-cell signaling complex that codelivers CD28 activation, dependent only upon the tumor's expression of the appropriate tumor associated antigen...

..These data suggested that NK cell TRAIL might regulate responses to vaccination by controlling the survival of Ag-loaded DC...

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..Overall, this study demonstrated the significant potential of suppressing tumors and other cellular targets expressing NKG2D-L by endowing T cells with innate NK cell-like function...

..Overall, these data not only confirm the key role that MyD88 plays in promoting tumor development but also demonstrate that inflammation-induced carcinogenesis and cancer immunoediting can indeed occur in the same mouse tumor model...

..Thus, these results indicated that NKG2D acted as a natural cytotoxicity receptor to stimulate perforin-mediated elimination of ligand-expressing tumor cells...

..Taken together, our results demonstrate that NK1.1+alphabetaTCR+ cell-based immune therapy can inhibit primary tumorigenesis...

..In summary, sequential tumor cell apoptosis and amplification of dendritic cell function by NKT cell agonists represents an exciting and novel approach for cancer treatment...

..These studies reveal that Tregs control multiple redundant elements of the immune effector response capable of inhibiting tumor initiation and underscore the importance of effectively targeting these cells in any cancer immunotherapy...

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..These results reflect a critical role for NK cells and gammadeltaTCR+ T cells in innate immune surveillance of B cell lymphomas, mediated by as yet undetermined pathway(s) of tumor recognition...

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..This study supports the use of humanized gene-modified T cells as a potential therapy for Le(Y+) malignancies...

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..T cell adjuvant treatment of day 8 metastatic disease resulted in dramatic increases in survival of mice, and this survival was significantly greater than that afforded by either doxorubicin, 5-fluorouracil, or herceptin...

..Overall, the results of this study have important implications for enhancing NK cell-based immunotherapies...

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..These data indicate that NK cells acquire KLRG1 on their surface during development, and this expression correlates with functional distinctions from other peripheral NK cells in vivo...

..These data confirm a role for GrzM in the host response to MCMV infection, but suggest that GrzM is not critical for NK cell-mediated cytotoxicity...

..This study provides critical new insight into how NKT cells can have such a major impact on immune responses, lasting many days beyond the initial stimulation of these cells...

..Our findings demonstrate a key role for IFN-gamma in innate and adaptive immunity triggered by CD80 expression on tumor cells...

..Thus CD27-CD70 interactions provide a key link between innate NK cell responses and adaptive T cell immunity...

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..In summary, this study significantly enhances our understanding of how NKT cells respond to primary and secondary antigenic challenge in vivo...

..These observations suggest that IAV infection of tumor cells may facilitate improved cross-presentation of tumor Ags and may be used to augment clinical vaccine efficacy...

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..These preclinical studies are an important proof of principle that human T cells may be genetically redirected to tumors in cancer patients...

..Overall, these data indicate the general role that IL-23 plays in suppressing natural or cytokine-induced innate immunity, promoting tumor development and metastases independently of IL-17A...

..These data support the use of gene-modified CD4(+) Th1 and CD8(+) T cells for mediating a sustained antitumor response...

..This study demonstrates that endogenous type I IFN is a central mediator of NK cell antitumor responses...

..These data raise the likelihood that granzyme M represents a third major and specialized perforin-dependent cell death pathway that plays a significant role in death mediated by NK cells...

..These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models...

..Finally, after experimentally verifying an optimized three-dimensional model, we have made predictions on the impact of two inherited perforin mutations of the C2 domain on calcium-dependent lipid binding and cell lysis...

..Overall, this study has highlighted the therapeutic potential of using combined transfer of antigen-specific gene-modified CD8+ and CD4+ T cells to significantly enhance T-cell adoptive transfer strategies for cancer therapy...

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..Thus, our results identify that CD27(high) NK cells are the dominant population recruited to the draining LN and NK cell recruitment requires endogenous IFN-gamma in coordinating with DC migration...

..In summary, our data demonstrate that DX5/CD49b is a poor marker for identifying CD1d-dependent NKT cells...

..p. RMA-erbB2(+) lymphoma. In summary, these data suggest that use of genetically modified NK cells could broaden the scope of cancer immunotherapy for patients...

..These results, combined with the fact that aged C57BL/6 TRAIL(-/-) mice showed no signs of spontaneous autoimmunity, strongly indicate that intrathymic negative selection occurs normally in the absence of TRAIL signaling...

..The ability of anti-CD1d mAbs to coincidently activate CD1d(+) APCs to release IL-12 and inhibit CD1d-restricted type II NKT cells makes CD1d an exciting new target for immunotherapy of cancer based on tumor immunoregulation...

..Thus, our results challenge the notion that IL-21 is a key factor in driving Th17 immunity and disease...

..This data suggests that perforin may mediate some suppression of epithelial carcinogenesis by intervening early in the tumor development process...

..Thus, IKDCs resemble NK cells functionally, and neither cell type could be induced to be effective antigen-presenting cells...

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..We were unable to demonstrate a role for TRAIL signaling in any of these models, suggesting that this pathway is not a critical factor for thymocyte negative selection...

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..Evidence clearly implicate that NKG2D recognition plays an important role in tumor immune surveillance...

..We assessed laboratory and clinical parameters in patients with myeloma treated with thalidomide as potential prognostic markers and looked for changes with therapy...

..We further show that immunodomination of PA(224-233)-specific TCD8+ by nucleoprotein 366-374-specific TCD8+ plays a critical role in the phenomena, and that this is unlikely to be mediated by TCD8+ lysis of APCs or other cells...

..1(-). Further elucidation of this NKT cell developmental pathway should prove to be invaluable for studying the mechanisms that regulate the development of these cells...

..This study is the first to describe the concomitant maturation of NK cell effector function with surface phenotype in vivo and implies an important defense role for NK cell TRAIL in the developing immune system...

..Therefore, although granule-mediated killing is of paramount importance for CTL-mediated lysis in vitro, some major in vivo effector mechanisms clearly are independent of perforin...

..These results in mice indicate that a rational monoclonal antibody-based therapy that both causes tumor-cell apoptosis through DR5 and activates T cells may be an effective strategy for cancer immunotherapy in humans...

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..Moreover, development of spontaneous tumors in p53(+/-) mice was also promoted by neutralization of TRAIL. These results indicated a substantial role of TRAIL as an effector molecule that eliminates developing tumors...

..Collectively, these findings suggest that IL-21 therapy may work optimally against tumors that can elicit a NKG2D-mediated immune response...

..These results suggested a role for blastocyst MHC in protecting TAP-deficient trophoblasts and tumor cells from NK cell attack in vivo...

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..Moreover, vaccination cured half of the CD1 and the majority of the MCP1 KO mice. The eradication of established p185(neu) carcinomas involves distinct mechanisms, each endowed with a different curative potential...

..Consequently, the efficacy of TRAIL therapy may vary depending on the location of the tumor metastases...

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..This study provides evidence for a functional interrelationship between DCs and NK cells during viral infection and defines some of the critical cytokines...

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..This suggests that recruitment/activation of J alpha 18(+) NKT cells is an important consideration during the immune therapy of early stage tumors...

..Our data clearly illustrate the double-edged sword of NKT cell-based therapy, showing that in some circumstances, such as when sub-clinical or chronic infections exist, iNKT cell activation can have adverse outcomes...

..These results suggest that the IFN-gamma-mediated inhibition of tumor angiogenesis is critically involved in the effector mechanisms of antitumor effects evoked by alpha-GalCer...

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..This proposal focuses clearly on a pivotal immune control mechanism that will influence many current and future immunotherapies. ..