Departments of Pediatrics and Immunology
Center for Cell and Gene Therapy
Texas Children’s Cancer Center
Baylor College of Medicine
Dr. Leonid Metelitsa
1102 Bates St., Suite 1760.06
Houston, TX 77030
Our research is focused on Va24-Ja18-invariant Natural Killer T (iNKT) cells. These cells are an evolutionary conserved sub-lineage of T cells with effector-memory phenotype that is characterized by reactivity to self- and microbial-derived glycolipids presented by monomorphic HLA class-I-like molecule CD1d. The emerging concept places the iNKT-CD1d system at the bridging point between innate and adaptive immunity that makes them an attractive target for developing new immunotherapeutic strategies in many diseases including cancer.
We found that infiltration of NKT cells in primary neuroblastomas was associated with good outcome, the phenomenon that was later extended to other types of cancer. Although the exact mechanisms of NKT cell localization to tumors are still poorly understood, recent reports by us and others have demonstrated that oncogenes such as MYCN in neuroblastoma can actively suppress the trafficking of NKT of and other effector T cells to the tumor site by regulating expression of chemoattractive signals in tumor cells. However, in those tumors that are infiltrated with NKTs, little is known about the mechanism by which these cells mediate anti-tumor activity. Interestingly, NKTs cannot kill neuroblastoma cells directly because the lack of CD1d expression in the latter. We have recently found that tumor-associated macrophages (TAMs) and their myelomonocytic precursors in bone marrow (BM) are the dominant CD1d-expressing subsets in primary tumors and metastatic BMs of neuroblastoma patients. TAMs promote tumors growth, and high expression levels of TAM-associated genes predict poor outcome in MYCN non-amplified tumors. Importantly, NKTs can selectively recognize and kill TAMs, suggesting that NKTs mediate anti-tumor responses indirectly via elimination of tumor-promoting TAMs. Our lab is currently focused on the investigation of this novel mode of anti-tumor immunity with the aim of developing effective NKT-based immunotherapeutic strategies against neuroblastoma and other types of cancer.
Postdoctoral Research Fellowship, Children’s Hospital Los Angeles, University of Southern California (mentor: Robert C. Seeger, MD), Los Angeles, CA
Ph.D. and Clinical Fellowship, N.N. Blokhin Memorial Cancer Research Center of Russian Academy of Medical Sciences, Moscow, Russia
M.D., Tver State Medical Academy, Tver, Russia
American Association of Immunologists (AAI)
Va24-Ja18-invariant Natural Killer T (iNKT) cells
NKT-based immunotherapeutic strategies
Our research is focused on Va24-Ja18-invariant Natural Killer T cells (NKTs). NKTs are an evolutionary conserved sub-lineage of T cells that are characterized by the expression of an invariant TCR œ-chain, Vœ24-Jœ18 and reactivity to self- and microbial-derived glycolipids presented by monomorphic HLA class-I-like molecule CD1d. The emerging concept places the NKT-CD1d system at the bridging point between innate and adaptive immunity that makes them an attractive target for developing new immunotherapeutic strategies in many diseases including cancer.
Despite the fact that the majority of solid tumors including neuroblastoma are CD1d-negative, the antitumor potential of NKTs has been demonstrated in numerous models of cancer. Our group made an original observation that NKT-cell infiltration of primary tumors was associated with good outcome in children with neuroblastoma, a finding that has been since extended to other malignancies. However, the mechanism by which NKTs mediate antitumor responses against CD1d-negative tumors had remained largely unknown. In a recent report we showed that NKTs co-localize with tumor-associated macrophages (TAMs) in primary neuroblastomas and upon recognition of tumor-derived glycolipids specifically kill TAMs in a CD1d-dependent manner (Song et al, J Clin Invest, 2009). Since TAMs provide a critical stromal support for tumor cell growth in neuroblastoma and many other types of cancer, NKT cell-mediated killing or inhibition of TAMs explains how NKTs may indirectly affect tumor growth.
We continue studies on the mechanisms of NKT cell localization and function at the tumor site. Our hypotheses are largely based on the findings that have been made in primary human tumors, tested in experimental in vitro and in vivo models, and are related to the disease outcome in cancer patients. The results will identify novel molecular targets for the development of effective immunotherapy of neuroblastoma and other types of cancer.
Our research is supported by competitive grants from NIH/NCI and CPRIT (State of Texas), and by Caroline Wiess Law Scholar Award (Baylor College of Medicine).
Dr. Leonid Metelitsa is a member of the Center for Cell and Gene Therapy (CAGT) research laboratories.
Leonid Metelitsa, M.D., Ph.D.
Katia Marinova, Ph.D.
Wei Huang, Ph.D.
Daofeng Liu, Ph.D.
Xiuhua Gao, Ph.D.
Andras Heczey, M.D.
Xin Xu, Ph.D.