The study, led by Dr. Leonid Metelitsa, associate professor of pediatrics – hematology/oncology at BCM and Texas Children’s Cancer Center, appears in the current issue of the Journal of Clinical Investigation.
Neuroblastoma is one of the most common solid tumors of childhood. Previous work by Metelitsa and his research colleagues showed that NKT cells localize to primary tumors in patients with neuroblastoma where they attack tumor-associated macrophages – a nonmalignant inflammatory subset of cells that support tumor growth.
“The NKT cells suppress tumor growth by going after the tumor-associated macrophages, but we know that eventually tumors find a way to grow anyway. We proposed that there must be some mechanism through which the tumor-associated macrophages are escaping from NKT cells,” said Metelitsa, who also is a member of the Center for Cell and Gene Therapy and the Dan L. Duncan Cancer Center at BCM.
They discovered that both the macrophages and the NKT cells localize to certain areas within the tumor with increased hypoxia, or areas with lower levels of oxygen. In areas of hypoxia, macrophages start producing new signals – such as the CCL-20 molecule – that lure NKT cells toward hypoxia and inhibit them from doing their tumor-suppressing job.
“Macrophages survive very well in areas of hypoxia and are able to do their job but NKT cells are inhibited and can no longer suppress macrophages,” he said. “We looked at potential means to overcome this inhibition and found that IL-15 protects NKT cells from hypoxia.”
Researchers created NKT cells that expressed the IL-15 protein, which is a known survival factor for NKT and other immune cells. They then injected the engineered cells into a mouse model with human metastatic neuroblastoma and human macrophages. The NKT cells with IL-15 had much higher anti-tumor efficacy against metastatic neuroblastoma in the humanized mouse model, Metelitsa said.
Others involved in this work include Drs. Daofeng Liu, Liping Song, Jie Wei, Amy N. Courtney, Xiuhua Gao, Ekaterina Marinova, Linjie Guo, Andras Heczey, Eugene Kim and Gianpietro Dotti, all of BCM, and Dr. Shahab Asgharzadeh, of the Children’s Hospital of Los Angeles and the Keck School of Medicine at the University of Southern California.
Funding for this research came from the National Institutes of Health, the U.S. Department of Defense, the Cancer Prevention and Research Institute of Texas and the Caroline Wiess Law Scholar Award.