Since its discovery in 1832, Hodgkin lymphoma has been an odd cancer marked by an odd history. Its discoverer, Thomas Hodgkin—a physician whose penchant for Quaker principles and liberal causes made him an eccentric in the medical world—had been dead for decades before the disease was recognized as a cancer. Hodgkin identified the swollen lymph nodes that are the physiological hallmarks of the disease. But it was the young medical student Dorothy Reed, exceptional simply for being a woman in a male-dominated field, who in 1902 identified the actual Hodgkin cancer cells. (The cells had been described four years earlier by Austrian pathologist Carl Sternberg, but he linked them to tuberculosis.)
More than a century later, Hodgkin lymphoma looks, if anything, even stranger. While most other tumors are teeming with cancer cells, each vying for blood and other resources, Hodgkin cells, also known as Reed–Sternberg cells, tend to be few and far between; indeed, they account for only five percent of cells in a tumor. Bloated in size, they lie, like so many queen bees, in a gelatinous mass of immune cells that, rather than attack the cancer cells, appear to feed them.
For years researchers have wondered, How do the Reed–Sternberg cells hold the immune system in thrall? And how do they pervert the system in the first place? A team of Dana–Farber Cancer Institute researchers, working with colleagues at other institutions, has found an intriguing answer. It is one that could lead, possibly within a few years, to new methods of diagnosing and treating the unusual lymphoma.
Though Hodgkin cancer cells are nestled in a mesh of immune cells, it is a strangely stitched fabric. Lacking are the very cells that would be most likely to attack the cancer cells, the Th1 cells and cytotoxic T cells. What remains is a friendly assortment: Th2 cells that release substances fueling the cancer cells’ growth and T regulatory (Treg) cells that further dampen the activity of cytotoxic and Th1 cells.
Seeking an explanation of this puzzling ratio—and, specifically, an answer to the question, What happens to the Th1 cells?—Przemyslaw Juszczynski, Jing Ouyang, Margaret Shipp, and colleagues compared Hodgkin cancer cells to other lymphoma cells. It now appears that the Hodgkin cells release high levels of a protein, galectin-1 (Gal1), that sends a death signal to nearby Th1 cells. Treg and Th2 cells appear to thrive in the presence of the protein. The findings appear in the Aug. 7 Proceedings of the National Academy of Sciences.
“We think that galectin-1 may function as a bodyguard for the tumor,” said Shipp, HMS professor of medicine. “The tumor is secreting something that is protecting it from its local surroundings and actually sculpts the immune response so it is not effective against the tumor.”
If so, then wrestling down the Gal1 strongman could restore the army of cancer-fighting Th1 cells. Gabriel Rabinovich, a researcher in Buenos Aires and a co-author on the paper, has successfully used such a Gal1-blocking strategy in living mice against a different cancer, melanoma. Buoyed by these findings, HMS research fellows in medicine Ouyang and Juszczynski, along with Shipp and her colleagues, have begun pursuing the approach for Hodgkin lymphoma.
“The thing we would love to see happen in the next two years is the development of neutralizing antibodies. We think we’re on our way,” said Shipp, who is also director of the Lymphoma Program at the Dana–Farber/Harvard Cancer Center. That will come as welcome news to the 8,000 to 10,000 people diagnosed annually, the majority of whom are young adults. Though Hodgkin lymphoma has a reputation for being one of the more curable cancers, the treatment—which consists of chemotherapy, radiation, or both—is notoriously toxic. A significant proportion of patients go on to develop secondary cancers.
Decades as an attending physician on a bone marrow transplant unit, where the goal is to get immune cells into the vicinity of tumor cells, had alerted Shipp to the ingenuity of her opponent, as had her research. “I’ve been working on the biology of lymphomas for a while, and one thing I’m increasingly appreciative of is the very, very sophisticated ways that tumors have figured out to essentially get what they need in a local microenvironment,” Shipp said.
Knowing that Reed–Sternberg cells are actually mutated B cells—incapable of carrying out normal functions yet, somehow, exerting a powerful effect on other immune cells—Juszczynski, Ouyang, Shipp, and Broad Institute colleague Stefano Monti set out to expose the cells’ genetic secret. Gene expression chips indicated that Reed–Sternberg cells express extremely high levels of Gal1—as much as 30 times the amount produced by other lymphoma cells. To see if the protein was actually responsible for killing the Th1 cells, the researchers used RNA interference to turn down Gal1 production in a line of Reed–Sternberg cells. Then they exposed the cells to a full complement of activated T cells, including Th1, Th2, and Treg cells. The Th1 and cytotoxic cells remained viable.
Still the question remained, What makes the Th1 cells so susceptible to Gal1? The researchers knew that the protein binds only to cell surface receptors that are decorated with a particular carbohydrate motif. Sure enough, the motif was present on Th1 cells, but not on Th2 or Treg cells. To see what causes the Reed–Sternberg cells to produce such high levels of Gal1, the researchers scoured the region on chromosome 22 where the Gal1 gene is located and found that its transcription is regulated by a constitutively activated AP1 enhancer.
Shipp and her colleagues at the Lymphoma Program, which includes people trained in running clinical trials, are poised to move the findings from the lab into the clinic. “As a group, we really hope to see this go all the way from bench to bedside,” she said. She does not foresee an anti-Gal1 strategy replacing more conventional approaches, but by restoring the fighting arm of a patient’s own immune system, it could lead to shorter, less toxic courses of treatment.
Gal1 antibodies, which are being produced in the lab by Ouyang and colleagues, could also aid in the diagnosis of Hodgkin lymphoma, which, with its unusually sparse distribution of cancer cells, can be difficult to diagnose conclusively. In fact, Jeffrey Kutok, a co-author on the PNAS paper, and colleagues at Brigham and Women’s Hospital are already using Gal1 antibodies to diagnose the disease.
Shipp has even bigger plans for the Gal1 antibody. “Though our focus has been on Hodgkin lymphoma, we think it’s very possible that this could have important implications,” she said. “We start with Hodgkin, but we wouldn’t be surprised if this becomes a much more broadly targeted protein.”
