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Massey researchers discover tumor cell target that can be inhibited to develop novel immunotherapy

Joseph Landry, Ph.D., with VCU graduate students Kimberly Mayes and Zeinab Elsayed

VCU Massey Cancer Center researchers have uncovered a mechanism used by tumor cells to hide from the immune system and pinpointed a cellular target that may lead to a novel form of immunotherapy.

Research conducted by Joseph Landry, Ph.D., and a team of Massey scientists, found that the chromatin-remodeling complex known as nucleosome remodeling factor (NURF) regulates gene expression in tumors. Chromatin remodeling refers to the cellular process of manipulating the structure, location or composition of nucleosomes, to better access DNA and control gene expression. Nucleosomes are a basic storage unit for DNA. 

The depletion of NURF in cancerous cells improved their ability to produce antigens which helped the immune system fight back against the disease, yielding promising results for the successful treatment of melanomas and breast cancers.

Published in Cancer Research, Landry’s team used mouse models with strong immune systems to determine that tumor growth slowed, and sometimes completely retreated, when cancer cells were depleted of NURF, and that T-cells more actively killed NURF-depleted tumor cells.

Landry, a member of Massey’s Cancer Molecular Genetics research program, said that ongoing research suggests that NURF is a viable target against which to develop a novel immunotherapy.  

“The combination of a more active T-cell that can now recognize better antigens could synergize to result in a much more powerful anti-tumor response,” Landry said.

Previous research has indicated that chromatin-remodeling complexes play a primary function in cell development, but are not typically required for cell survival. They have also been shown to act as major drivers for the growth of a number of cancers.

The immune system is programmed to detect and destroy cancer cells through the employment of T-cells which seek out antigens, or molecules on the surface of cells, that represent toxic or foreign substances. However, many tumors adapt by suppressing antigens and disguising other stress indicators, effectively becoming invisible to immune response.

Landry’s study set out to see if there were specific epigenetic regulators, which are enzymes that help control gene expression, that were involved in shielding tumor cells from the immune response system, and preliminary data from other studies demonstrated that NURF might be a primary suspect.

Although much research had previously been done on the functions of chromatin-remodeling complexes, there were no previous studies on NURF’s role in mammals. Landry’s team was able to eliminate NURF in mouse models by disabling its primary subunit, bromodomain PHD-finger containing transcription factor (BPTF).

Using cancer cell lines that had already evolved the means for suppressing antigenicity, which is the ability to influence the production of proteins that fight certain bacteria and viruses, they compared mice with an immune system to those without one and found that the NURF-depleted tumor cells in the immune competent models grew at a significantly slower rate.

Once it became clear that the immune system played an integral function in the detection of NURF-depleted tumors and growth reduction, they performed a microarray analysis to measure gene expression.

“We observed that, in the NURF knockdown cells, there was an increase in the expression of the genes that are involved in antigenicity,” Landry said.

Using in vitro techniques, it became apparent that the NURF complex altered the chromatin structure of antigen-processing genes to suppress their expression.

“We can then re-express those genes by depleting NURF. That results in improved antigenicity, and then the T-cells in mice with NURF knockdown tumors expand to recognize and kill the tumors more effectively,” Landry said.

Most existing immunotherapies infrequently demonstrate long-term antitumor impacts because of tumor adaptation. Landry said that a NURF-inhibiting form of immunotherapy might differ from the majority of immunotherapies in that it could directly target the tumor cell as opposed to impacting T-cell functions, and therefore could be used to augment existing immunotherapies to achieve more long-term antitumor immunity.

Landry believes that NURF inhibition could have significant benefits for the successful treatment of melanomas and breast cancers. His long-term goal is to partner with pharmaceutical companies to conduct clinical trials at VCU.

Landry conducted his research with the help of two graduate students, Kimberly Mayes and Zeinab Elsayed. He also collaborated with Catherine Dumur, formerly an associate professor at VCU Department of Pathology; and Shawn Wang, Ph.D., professor at VCU Department of Human and Molecular Genetics.

The study was funded by the National Cancer Institute (P30 CA016059), VCU and was an early career scholar from the V Foundation for Cancer Research.

Landry is an assistant professor in the Department of Human and Molecular Genetics and a member of the VCU Institute of Molecular Medicine at the VCU School of Medicine.

Written by: Blake Belden

Posted on: December 16, 2016