Leonid S. Metelitsa, MD, PhD
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 (e.g. D. Liu et al., J. Clin. Invest. 2012; A. Heczey et al., Blood, 2014). 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, CPRIT , Leukemia & Lymphoma Society, Alex’s Lemonade Stand Foundation, and Cookies for Kids’ Cancer Foundation.