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Crowe, N. Y., Smyth, M. J. & Godfrey, D. I. A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. J. Exp. Med. 196, 119-127

Department of Pathology and Immunology, Monash University Medical School, Melbourne, Victoria 3181, Australia.
Journal of Experimental Medicine (Impact Factor: 13.91). 08/2002; 196(1):119-27. DOI: 10.1084/jem.20020092
Source: PubMed

ABSTRACT Natural killer (NK) T cells initiate potent antitumor responses when stimulated by exogenous factors such as interleukin (IL)-12 or alpha-galactosylceramide (alpha-GalCer), however, it is not clear whether this reflects a physiological role for these cells in tumor immunity. Through adoptive transfer of NK T cells from wild-type to NK T cell-deficient (T cell receptor [TCR] Jalpha281-/-) mice, we demonstrate a critical role for NK T cells in immunosurveillance of methylcholanthrene (MCA)-induced fibrosarcomas, in the absence of exogenous stimulatory factors. Using the same approach with gene-targeted and/or antibody-depleted donor or recipient mice, we have shown that this effect depends on CD1d recognition and requires the additional involvement of both NK and CD8+ T cells. Interferon-gamma production by both NK T cells and downstream, non-NK T cells, is essential for protection, and perforin production by effector cells, but not NK T cells, is also critical. The protective mechanisms in this more physiologically relevant system are distinct from those associated with alpha-GalCer-induced, NK T cell-mediated, tumor rejection. This study demonstrates that, in addition to their importance in tumor immunotherapy induced by IL-12 or alpha-GalCer, NK T cells can play a critical role in tumor immunosurveillance, at least against MCA-induced sarcomas, in the absence of exogenous stimulation.

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    • "Moreover, a number of reports have suggested that iNKT cells play protective as well as tolerogenic roles in tumor immunity [24] [25] [26] [27] [28] [29]. In addition, infiltration of iNKT cells is a prog‐ nostic indicator for colorectal cancer metastasis [29] "
    "Immune Response Activation", Edited by Guy Huynh Thien Duc, 05/2014: chapter Chapter 8;
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    • "Moreover, a number of reports have suggested that iNKT cells play protective as well as tolerogenic roles in tumor immunity [24] [25] [26] [27] [28] [29]. In addition, infiltration of iNKT cells is a prog‐ nostic indicator for colorectal cancer metastasis [29] "
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    ABSTRACT: The roles of natural killer (NK)T cells in intestinal immunity have not been sufficiently investigated. The bowel possesses its own unique mucosal immune system, the gut-associated lymphoepithelial tract (GALT). In this review, we focused on CD1d-independent invariant type NKT (iNKT) cells as modulators of GALT. iNKT cells have a restricted invariant T-cell receptor (TCR) Vα24 chain paired with Vβ11 chain. In addition to T helper (Th)1 cytokines, such as IFN-γ, iNKT cells can produce anti-inflammatory Th2 cytokines, such as interleukin (IL)-4. Although invariant NKT cells are rare in normal small-intestine mucosa, they have been observed in intestinal allografts during rejection. Infiltrating iNKT cells release IL-4 and IL-5, Th2-related cytokines that antagonize the Th1 responses that induce acute cellular rejection. Also, iNKT cells form an immunological barrier against parasite infection. We found that CD1d +cells are actually localized in the lamina propria of the villi in the human intestine and they may present the antigen for the recruited iNKT cells. On the other hand, a small number of invariant NKT cells are resident in the normal colorectal mucosa. iNKT cells are involved in defense against colorectal tumor progression and meta‐ stasis through the apoptosis-inducing molecule Fas ligand (FasL). Their numbers increase markedly in colorectal carcinomas. Increased iNKT cell infiltration in colorectal carcinomas is an independent favorable prognostic factor. iNKT cells probably play an important role in the pathogenesis of ulcerative colitis. Thus, iNKT cells are modulators of bowel mucosal immunity.
    Edited by Guy Huynh Thien Duc, 05/2014; Intech., ISBN: 978-953-51-1374-4
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    • "In the equilibrium phase, cancer cells maintain a balance with the immune system where they are able to avoid immune-mediated destruction but are not able to progress [40, 41]. "
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    ABSTRACT: Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25–50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease. Corrigendum to “Sarcoma Immunotherapy: Past Approaches and Future Directions”
    Sarcoma 03/2014; 2014(10):391967. DOI:10.1155/2014/391967
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