The potential importance of CD1d-restricted V124-invariant Natural Killer T cells (NKTs) for antitumor immunity and immunotherapy has been demonstrated in multiple models of cancer as well as in recent oncology clinical trials. Recent findings by our own and other labs suggest that while NKTs lack direct effect on tumor cells in the majority of solid tumors, they mediate antitumor immune responses via specific interactions with CD1d- positive subsets of myelomonocytic cells. We have recently demonstrated that one way by which NKTs may control tumor growth is by specific recognition and killing of tumor-associated macrophages (TAMs), thereby removing essential IL-6-STAT3-mediated growth support from tumor cells. Our preliminary data suggests that there is a stepwise CCL2- and CCL20-mediated NKT-cell localization to the tumor site, in which NKTs interact with CD1d+ TAMs and immature dendritic cells (iDCs) in the context of the tumor microenvironment. We have found that monocytic cells strongly up-regulate CCL20 expression in response to hypoxia-mediated signal(s) from neuroblastoma (NB) cells, leading us to hypothesize that tumor hypoxia regulates NKT cell localization and innate antitumor activity in NB. Because CCL20 is also a potent chemoattractant for iDCs, NKT cell interaction with CD1d+ iDCs at the tumor site may lead to the generation of protective adaptive immune response. The following specific aims will test these hypotheses: 1) to examine the mechanism by which tumor hypoxia regulates NKT cell localization and innate anti-tumor activity in NB;2) to examine the role of NKT cell interaction with CD1d+ myeloid cells at the tumor site in the mechanism of adaptive anti-tumor immune response against NB. Using established in our lab humanized NB/TAM model and human ex vivo expanded NKTs, we will evaluate the role of hypoxic signaling in CCL20-dependent NKT-cell co-localization with TAMs and the role of NKT cell interaction with TAMs in the mechanism of innate NKT cell-mediated antitumor activity. Then, using NB9464-OVA murine NB model, we will study how NKT-cell interaction with CD1d+ myeloid cells at the tumor site may lead to activation and maturation of iDCs, followed by improved presentation of tumor-derived antigens to CD8 T cells and generation of protective adaptive immunity. The results of the proposed investigation are expected to reveal novel mechanisms that govern NKT-cell localization to the tumor site and their function in the antitumor immunity.

Public Health Relevance

The proposed investigation will continue to investigate the mechanism of NKT cell homing to the tumor site in neuroblastoma, one of the most common and deadly type of cancer in children. We will examine how NKT cells regulate innate and adaptive antitumor immune responses in the context of the tumor microenvironment. The results may lead to new immunotherapeutic strategies and clinical trials in neuroblastoma and other types of cancer in children and adults.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA116548-09
Application #
8585829
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Howcroft, Thomas K
Project Start
2005-07-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
9
Fiscal Year
2014
Total Cost
$211,012
Indirect Cost
$76,180
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Liu, Daofeng; Song, Liping; Wei, Jie et al. (2012) IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity. J Clin Invest 122:2221-33
Liu, Zheng; Courtney, Amy N; Metelitsa, Leonid S et al. (2012) C-Glycosphingolipids with an exo-methylene substituent: stereocontrolled synthesis and immunostimulation of mouse and human natural killer T lymphocytes. Chembiochem 13:1733-7
Metelitsa, Leonid S (2011) Anti-tumor potential of type-I NKT cells against CD1d-positive and CD1d-negative tumors in humans. Clin Immunol 140:119-29
Xiong, Guosheng; Husseiny, Mohamed I; Song, Liping et al. (2010) Novel cancer vaccine based on genes of Salmonella pathogenicity island 2. Int J Cancer 126:2622-34

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