- The immune system has mechanisms for detecting and destroying cancer cells.
- A molecule that helps cancer cells survive genetic damage might also help malignant cells avoid being killed by the immune system.
- The findings could improve the effectiveness of immune therapies for cancer.
COLUMBUS, Ohio - A molecule that helps cancer cells evade programmed self-destruction, an internal source of death, might also help malignant cells hide from the immune system, an external source of death. A new study by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) shows that a molecule called nuclear factor kappa B (NF-kB) helps cancer cells by suppressing the immune system's ability to detect and destroy them. The molecule regulates genes that suppress immune surveillance mechanisms, including the production of cells that inhibit the immune response. The research suggests that immune therapy for cancer might be more effective if combined with drugs that inhibit NF-kB. They also provide new details about how interactions between cancer cells and noncancer cells assist tumor growth. The findings are published in the journal Cell Reports. "We've long known that NF-kB promotes cancer development by subverting apoptosis, an internal safety mechanism that otherwise would cause cancer cells to self-destruct," says principal investigator Denis Guttridge, PhD, professor of molecular virology, immunology and medical genetics and of molecular and cellular biochemistry. "This study shows that NF-kB might coordinate a network of immune-suppressor genes whose products enable tumor cells to evade adaptive immunity," he adds. "Therefore, inhibiting NF-kB will might make tumor cells more vulnerable to elimination by the immune system." A 2009 study by the same researchers showed that NF-kB helps normal cells in DNA repair, which may prevent them from harming the body. However, it is hard to understand why such a molecule might act differently in cancer cells, where NF-kB is typically always in an active state. For this study, Guttridge, first author David J. Wang, who developed many of the study's concepts, and their colleagues monitored NF-kB activity during tumor development using mouse embryonic fibroblasts and two mouse models. Key technical findings include:
- During early tumor development, macrophages - innate immune cells - migrate into the tumor;
- NF-kB enables cancer cells to survive the pro-apoptotic influence of tumor necrosis factor that is released by tumor infiltrating macrophages;
- NF-kB may also regulate a number of genes related to immune suppression, particularly TGF-beta, IL-10, GM-CSF, G-CSF and VEGF.
- In cancer cells with active NF-kB, shutting down TGF-beta expression removed its immune suppressive influence and delayed tumor growth, evidence that TGF-beta is a gene regulated by NF-kB that contributes to tumor development.
"Overall, our findings demonstrate that NF-kB might play a pivotal role in enabling cells to evade surveillance by both innate and adaptive immune cells," Guttridge says. Funding from the NIH/National Cancer Institute (grant CA140158) supported this research. Other Ohio State researchers involved in this study were Nivedita M. Ratnam and John C. Byrd. The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 228-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S.News & World Report.
A high quality JPEG of Denis Guttridge, PhD, is available here. Contact: Darrell E. Ward, Wexner Medical Center Public Affairs and Media Relations,614-293-3737, or Darrell.Ward@osumc.edu
