When good immune cells turn bad

September 21, 2017

Investigators at the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles have identified new findings about an immune cell - called a tumor-associated macrophage - that promotes cancer instead of fighting it. They have identified the molecular pathway, known as STAT3, as the mechanism the immune cell uses to foster neuroblastoma, a pediatric cancer, and have demonstrated use of a clinically available agent, ruxolitinib, to block the pathway. Results of the study were published in the journal Oncotarget on September 20.

Neuroblastoma is the second most common solid tumor effecting children. Individuals with high-risk disease have a mortality rate of approximately 50 percent. Certain conditions are associated with high-risk disease. High levels of some chemicals involved with inflammation and the presence of an immune cell called a tumor-associated macrophage (TAM) are associated with high-risk disease and lower survival rates. Macrophages are a type of immune cell that typically function to battle disease, not encourage it.

"The macrophages are essentially co-opted by the tumor cells to help them grow," said Shahab Asgharzadeh, MD, director of the Basic and Translational Neuroblastoma program at CHLA and lead investigator of the study. "We're trying to find out more about the mechanisms that enable TAMs to help cancer grow so that we can target the pathways they use and block their pro-tumor effect."

The team wanted to find out whether effective therapeutic approaches for children with neuroblastoma could be based on targeting inflammation-associated biologic pathways in the area surrounding the tumor, called the tumor microenvironment. Using a mouse model to examine the activity of TAMs within the tumor microenvironment, the research team observed the "recruitment and polarization" of TAMs which enhance the ability of neuroblastoma to spread and grow. They found that TAMs exhibit a dual role - not only nourishing the neuroblastoma but also effectively helping them to evade the "good immune cells" seeking to kill the tumor cells.

To study the effect of TAMs on neuroblastoma cell growth and proliferation, the investigators co-cultured both mouse and human neuroblastoma cells with TAMs and found a significant increase compared to tumor cells without TAMs.

In an effort to find out what the TAMs were secreting that caused stimulation of tumor cells, the investigators targeted IL-6, an immune substance known to cause proliferation of certain types of cancer. Using a mouse model that lacked IL-6, they still observed increased tumor growth. In these experiments, they noted activation of the STAT3 cell-signaling pathway - known to promote tumor growth preceding an increase of MYC - a gene that drives many types of cancer.

These findings led them to target the STAT3 pathway. Using a clinically available drug, ruxolitinib, known to block the STAT3 pathway, the investigators co-cultured both human and mouse TAMs and neuroblastoma cells. They observed that the immune cells no longer supported tumor growth.

"Targeting STAT3 may be a promising approach to block interactions between tumor cells and the 'traitorous' immune cells, and a way to improve outcomes for children with high-risk neuroblastoma," said Asgharzadeh, who is also a professor of pediatrics with the Keck School of Medicine of the University of Southern California.

According to Asgharzadeh, the next step is to combine agents that block the STAT3 pathway with drugs that have been effective in treating neuroblastoma.
-end-
Other contributors to the paper include Michael D. Hadjidaniel, Sakunthala Muthugounder, Long T. Hung, Michael A. Sheard, Soheila Shirinbak, Randall Y. Chan, Rie Nakata, Lucia Borriello, Jemily Malvar, Rebekah J. Kennedy, Hiroshi Iwakura, Takashi Akamizu, Richard Sposto, Hiroyuki Shimada, and Yves A. DeClerck, all of Children's Hospital Los Angeles, along with Hiroshi Iwakura and Takashi Akamizu of the First Department of Medicine, Wakayama Medical University in Japan. Asgharzadeh, Sposto, Simada and DeClerck are also faculty members of the Keck School of Medicine of USC. The research was supported by grants from the Department of Defense (CDMRP10669916), (W81XWH-12-1-0571), the T.J. Martell Foundation, the Norris Foundation, the Nautica Malibu Triathlon and the National Institutes of Health U54 (5U54CA163117).

About Children's Hospital Los Angeles

Children's Hospital Los Angeles has been ranked the top children's hospital in California and sixth in the nation for clinical excellence with its selection to the prestigious U.S. News & World Report Honor Roll. CHLA is home to The Saban Research Institute, one of the largest and most productive pediatric research facilities in the United States. Children's Hospital is also one of America's premier teaching hospitals through its affiliation with the Keck School of Medicine of the University of Southern California since 1932. For more information, visit CHLA.org. Follow us on Twitter, Facebook, YouTube, LinkedIn and Instagram, and visit our child health blog (CHLA.org/blog) and our research blog (ResearCHLABlog.org).

Children's Hospital Los Angeles

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.