Peter Savage (left) and faculty member James Allison discovered a previously unknown immune response to cancer in mice.

They Were Surprised to Find That Common, Ubiquitous Molecule Triggers the Response

Using mice that are genetically engineered to develop prostate cancer in a manner that mimics the formation of human prostate cancers, investigators at Memorial Sloan-Kettering Cancer Center have found a previously unknown immune response to tumor cells. The research may eventually provide clues to how the immune system recognizes cancer in humans and could suggest ways to train it to target cancer cells.

"We have always suspected that the immune system is able to mount an attack against primary cancer cells," said James P. Allison, Chair of the Immunology Program in the Sloan-Kettering Institute and the study's senior author. "The newly revealed immune response was found to ultimately be weak and ineffective, but once we learn more about how it works, we may find a way to strengthen it."

The response was discovered when Peter A. Savage, a postdoctoral fellow in Dr. Allison's laboratory and the study's lead author, began analyzing T cell receptors found in these specially engineered mice. (T cell receptors are responsible for recognizing antigens, proteins on the surface of cells that do not normally appear in the body.) The investigators learned that most of the mice had tumor-infiltrating T cells that had the same type of T cell receptor, which suggested that there was a dominant target in the tumors that the immune system was recognizing and to which it was responding.

What was most surprising about the finding was the antigen molecule that triggered the T cell response: a peptide (protein fragment) of a molecule called histone H4, which naturally occurs in every cell in the body. Histone H4 is one of five histone proteins that, along with DNA, create chromatin -- the molecular complex that makes up chromosomes and enables long strands of DNA to wind and fold themselves to fit inside the nucleus of the cell. Histones also play a role in gene regulation. But they normally exist only deep inside cells where the immune system wouldn't be able to see them, not on the cell surface, as was the case with these peptides.

"One of the big mysteries is why prostate cancer cells are revealing this peptide in a way that other cells are not," said Dr. Savage. "We don't yet know if histone H4 will be found in human prostate tumors, and whether it will be found in other cancers as well."

A large percentage of cancer research is done by injecting human tumor cells into mice and then monitoring the cells' growth, which does not replicate the physiological way that tumors form in humans. The mice in this study were engineered to carry genetic mutations that caused prostate tumors to form naturally and gradually and change over a period of time in the same way that tumors evolve in humans. These mouse models allow the research team to study the ongoing immune response at different stages of the disease.

"The histone-reactive T cells that we found are mounting a partial response," Dr. Savage said. "They are recognizing the histone H4 antigen, differentiating, and infiltrating the tumors, but they're not protecting the mice against cancer. This is exactly what we see in patients. Cancer patients have T cells that are reactive to tumor antigens, but the T cells' responses don't protect people from developing cancer. Now we will be able to do molecular and cellular experiments in the laboratory to find out why that is the case."

One of the next steps of the research is to determine whether prostate tumor cells in humans also carry the histone H4 antigen on their surface. Dr. Allison and his collaborators are analyzing blood samples from cancer patients to look for evidence of T cells with the same specificity. If they are found, it's possible that these T cells could be used as a diagnostic marker in the blood. But perhaps more important, they will teach investigators much about how the immune system responds to cancer in patients.

"These T cells become functionally inactivated, but they are still there," said Dr. Allison, who is also Director of the Ludwig Center of Cancer Immunotherapy and holds the David H. Koch Chair in Immunologic Studies. "I'm thinking there might be some way to remobilize them, which could improve our chances of helping the immune system to attack tumors." Harnessing the immune system for the purpose of fighting cancer is an important area of cancer research, and one that Dr. Allison has focused on for many years.

The research was published in January in Science. Other Memorial Sloan-Kettering authors on the study were Kathleen Wojnoonski in Dr. Allison's laboratory and Elyn Riedel of the Department of Epidemiology and Biostatistics. Researchers from Drexel University and the University of California, Berkeley, as well as Achim Jungbluth from the Ludwig Institute for Cancer Research also contributed to the work. [PubMed Abstract]