Alexander “Sasha” Rudensky is Chair of the Immunology Program in the Sloan Kettering Institute at Memorial Sloan Kettering, Director of MSK’s Ludwig Center for Cancer Immunotherapy, and a Howard Hughes Medical Institute investigator. A native of Russia, he joined MSK in 2008 after many years at the University of Washington.
An internationally recognized leader in the field of immunology, Dr. Rudensky has just been appointed to the National Academy of Medicine, adding to his many other honors — including membership in the American Academy of Arts and Sciences and the National Academy of Sciences. He also was one of this year’s recipients of the William B. Coley Award for Distinguished Research in Basic Tumor Immunology from the Cancer Research Institute and last month was named a Thomson Reuters Citation Laureate.
We spoke to him recently about his research.
What are regulatory T cells and why are they important?
T cells, also known as T lymphocytes, are white blood cells. They are the components of the blood that control the body’s response to infections. A series of studies conducted over the past four decades suggest that regulatory T cells are the subset of white blood cells that restrain responses of the rest of the immune system.
Research in mice in the early 2000s showed that animals genetically unable to make regulatory T cells suffered from inflammation and a number of autoimmune diseases, such as diabetes and thyroiditis [in which the body attacks its own thyroid gland]. These findings provided genetic proof that the role of regulatory T cells is to maintain order in the immune system.
Regulatory T cells have also been implicated in maintaining maternal-fetal tolerance during pregnancy — that is, they prevent the mother’s immune system from attacking the fetus — and in limiting collateral damage associated with immune responses to infection. So they are really keepers of balance and of inflammatory responses in a variety of settings.Back to top
What role do regulatory T cells play in cancer?
Regulatory T cells prevent the immune system from attacking tumors, which might otherwise be recognized as foreign or as different from “self.” We believe tumors can surround themselves with regulatory T cells to protect themselves from attack and also likely send signals to grow or expand regulatory T cells that are already nearby.
There is another possibility, which is that tumors help other kinds of white blood cells transform into regulatory T cells.
We think that regulatory T cells in tumors have multiple functions, not only in suppressing the immune response but also in enabling tumor growth.Back to top
How could our understanding of regulatory T cells lead to the development of new cancer immunotherapies?
One strategy for fighting cancer is to target a protein called FOXP3, which enables other T cells to differentiate into regulatory T cells. People with a rare autoimmune disease called IPEX have a dysfunctional version of FOXP3, which leads to aggressive autoimmune inflammation in a variety of organs and tissues.
In people with cancer, using a drug to turn off FOXP3 could prevent the tumor from recruiting regulatory T cells, which in turn might enable the immune system to recognize the tumor and attack it or to stop the tumor from providing support for its growth.
It’s possible that targeting FOXP3 could negatively affect the immune system, but most cancer treatments come with some sort of cost. However, in our preclinical work in mice, we found that temporary depletion of regulatory T cells didn’t result in significant damage to tissues and vital organs. But it did significantly slow down progression of disease in a mouse model with a highly aggressive cancer that was not thought to be receptive to other immunotherapy treatments.
There are already clinical trials under way that focus on targeting regulatory T cells through other means. One trial at MSK, being led by Jedd Wolchok and George Plitas, is evaluating an antibody called KW-0761 in patients with solid tumors. This antibody targets another protein on regulatory T cells, called CCR4, which appears in high levels in cells that are activated and is designed to eliminate those cells.
It may also be beneficial to combine treatments that block regulatory T cells with other types of therapy, such as radiation therapy, chemotherapy, targeted therapy, or maybe even other immunotherapeutic optionsBack to top
Are there implications for treating conditions other than cancer?
We think that boosting regulatory T cell numbers and activity may be an effective strategy for treating graft-versus-host disease, a potentially fatal consequence of stem cell or bone marrow transplant that arises when white blood cells from the donor attack the recipient’s tissues. Activating and expanding these cells may also provide an answer to graft rejection in organ transplantation.
Similarly, for autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis and inflammatory disorders like inflammatory bowel disease, boosting the activity of regulatory T cells and increasing their numbers may help relieve symptoms.Back to top
What are the next steps for your research, and what do you hope to accomplish over the next few years?
We would like to understand the function of regulatory T cells in diverse biological contexts — not only in cancer but also in the context of normal tissues — and further explore their function in tissue maintenance and tissue protection.
We also want to understand differentiation of the cells as a basic question in developmental biology: How do cells choose what they will become, how is that choice maintained, and how is it being executed in a variety of environments in which cells have to respond to environmental challenges?
In addition, we’d like to know whether regulatory T cells, like other types of immune cells, maintain memories of past challenges that make them respond differently when those challenges arise again.Back to top