Moffitt Center unlocks mystery protein in tumors

In one of the biggest advances to come from the H. Lee Moffitt Cancer Center and Research Institute in its 16-year history, researchers have identified a key protein in tumors that allows them to flourish undetected by keeping their presence a secret from the body’s immune system.

The breakthrough was discovered in a study titled “Regulation of the innate and adaptive immune responses by Stat3 signaling in tumor cells,” conducted by Hua Yu, an associate professor in the Immunology Program at Moffitt.

“Cancer is allowed to wreak havoc on the body’s immune system because it knows how to fool the body’s defensive arsenal,” said Jack Pledger, associate center director for basic science. “The discoveries of Dr. Yu give us vital information about how tumors stay invisible. It opens the way for new treatments to help flush the cancer cells into the open, so the body’s army against disease can destroy them.”

The protein that was identified is called Stat3 and is part of the STAT family of proteins that regulates genes in the body. Stat3 is a protein that is in every cell. In normal cells, Stat3 is tightly regulated, but in oncogenic, or cancerous, cells it is continuously activated. This allows tumors present in the body to hide from the immune system and flourish.

“In normal cells, (Stat3 proteins) turn on and off very rapidly, but in cancer cells they are continuously on. When they are on, they block the immune system from responding. We found that this protein is on because many of the oncogenic or cancerous causing proteins can activate this protein naturally,” Yu said.

The results of the study conducted by Yu showed that a tumor activation of Stat3 secretes factors that inhibit the body’s immune responses by keeping dendritic cells from maturing.

“Dendritic cells are very important to activate T-cells and anti-tumor responses mainly coming from T-cells,” Yu said.

Dendritic cells are immune cells and form part of the mammal immune system. They are present in those tissues that are in contact with the environment such as in the skin, the lining of the nose, lungs, stomach and intestines. They have long spiky arms, called dendrites, hence the name.

Dendritic cells constantly sample their surroundings for viruses and bacteria. Once they have captured a foreign element in the body, they cut its proteins into small pieces and present those fragments at their cell surface. Then, they travel through the blood stream to the spleen or through the lymphatic system to a lymph node. Here, they activate helper T-cells, killer T-cells and B-cells by presenting them with the pieces of the foreign element. Depending on the type of invader, this process results in an immune response involving antibodies or killer cells.

The results of the study also showed that the activation of Stat3 blocks the expression of inflammatory mediators required to trigger the immune system.

Various inflammatory mediators are released by immune cells during times when harmful agents invade the body. Early scientists considered inflammation as the body’s primary defense system. However, inflammation is more than just a simple defense system, because if left unchecked, it can lead to debilitating diseases such as arthritis or even death.

Various molecules released by the body’s immune cells control the development of inflammatory reactions. The immune cells act as the body’s soldiers, and they guard the body against attacks by releasing weapons in the form of inflammatory mediators.

Now that the medical community has exposed one of the key elements that allows tumors to hide from the immune system, Yu said Moffitt hopes they can develop a new generation of chemotherapy that specifically targets the protein Stat3 in order to expose tumor cells to the immune system.

Yu’s co-authors on the study include Drew Pardoll from the Johns Hopkins University School of Medicine and Richard Jove and William Dalton from Moffitt. Other authors that participated in the project are Tianhong Wang, Guilian Niu, Lyudmilla Burdelya and Marcin Kortylewski.

One specific type of therapy that Yu mentioned was molecular targeting. It differs from most types of chemotherapy in that it specifically targets certain molecules to attack instead of killing off all molecules indiscriminately.

“Here, we are targeting a very specific molecule in the cancer cells. A (scientist) targets it and (the scientist) knocks out the function of this molecule, which is responsible for tumor cell growth and which helps to hide tumor cells from immune detection,” Yu said.