FEATURED INVESTIGATOR
THOMAS SETH KUPPER, MD

The focus of Dr. Kupper’s research is the immune system; how it recognizes invaders and how our largest body organ, the skin, protects the individual from the external environment. His laboratory investigates both innate immunity, which includes the complement system, cytokines, and toll-like receptors, andadaptive immunity, which is provided by T and B lymphocytes. “In other words,” Dr. Kupper explains, “we are interested in all parts of the immune system that are customized to deal with foreign and infectious pathogens, as well as cancers that arise within the microenvironment of the skin.” One of Dr. Kupper’s chief research interests is a malignancy of the skin-homing lymphocytes called cutaneous T-cell lymphoma (CTCL). This is a cancer of CD4+ T cells, a type of cell that normally acts as an important part of the skin’s adaptive immune system. In CTCL, these cells retain the ability to home to the skin, where they grow and cause dermatologic symptoms. Eventually, some tumors develop the capacity to spread and grow into other tissues in addition to the skin, at which point they become even more significant clinical problems, sometimes causing death. Dr. Kupper’s group is focused on gaining a more complete picture of the biology of CTCL, which is expected to permit the development of better therapies for both localized and systemic disease.

Background

A native of southern California, Dr. Kupper received his undergraduate degree from the University of California, Los Angeles. He attended Yale Medical School, where he also trained as a resident physician. After spending several years at Washington University in St. Louis, Dr. Kupper came to the Brigham and Women’s Hospital in 1992, where he is now chairman of the department of dermatology; principal investigator of the cutaneous SPORE grant, a multicenter research effort; as well as Director of the Biomedical Research Institute.

Research

With skin cancer on the rise, Dr. Kupper’s group researches the ways that cancers arise and how they can be treated in the skin. “Everyone has a large population of T-cells that is specially adapted to protect the skin from pathogens,” Dr. Kupper explains. “These T-cells live in the skin. They circulate out occasionally and come back in, but they’re pretty much hard-wired to stay there. In addition to pathogens, such as viruses, bacteria, and fungi, skin cells are exposed to mutagens like UV light which cause genetic changes.” These genetically altered cells express different surface molecules that are recognized and eliminated by cutaneous T cells. When the immune system is suppressed, such as in transplant patients, these cells are not eliminated normally, and there is a consequent increase in skin cancers. “In CTCL,” Dr. Kupper says, “genetic or epigenetic changes immortalize a single skin-homing T cell. Because these cells retain the ability to home to the skin and to be activated by cues that are received from the environment, patients present with dermatologic complaints, which may take the form of a rash or sometimes a tumor. Local therapy is effective in treating these tumor cells in the skin, but like normal skin-homing lymphocytes, the tumor cells also circulate widely throughout the body. Thus, while therapy delivered to the skin can bring relief, the tumor persists and is likely to eventually recur. One key in this disease is to uncover the genetic changes that transform the cell, in the hope that we might be able to come up with therapies to treat the disease systemically as well as locally. Another approach takes advantage of the similarity of CTCL cells to normal skin-homing T cells. By understanding the signals and pathways that govern the behavior of normal skin-homing T cells, we may be able to develop therapies that interrupt these same pathways in tumor cells to therapeutic advantage.”

 

Laboratory

In addition to both senior and junior faculty members, Dr. Kupper’s laboratory is home to several medical and postgraduate students as well as undergraduate interns and skilled technicians. Dr. Kupper seeks out individuals who are both enthusiastic and excited about this area of research. Asked to explain what he values most, Dr. Kupper responds, “Training is less important to me than several things. In addition to enthusiasm and excitement, I place a high value on dogged determination and the ability to really think out of the box creatively. If you have somebody with these attributes, you have a successful scientist.”

 

funding

Dr. Kupper’s laboratory is principally funded by the National Institutes of Health and receives some private philanthropic support.

Collaborations

Dr. Kupper and his colleagues are involved in many local, national, and international collaborations.

Importance of Being at the Brigham

“I think the unique strength of the Brigham is that you have in the same institution some of the very best clinicians in the world and some of the very best scientists in the world,” Dr. Kupper says. “I have thought for years that the Brigham is an unappreciated research powerhouse, particularly in translational research, the likes of which there are only a small handful in the entire country.”

Selected References
  1. Liu L, Zhong Q, Tian T, Dubin K, Athale SK, Kupper TS.  Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell–mediated immunity.  Nature Medicine. 2010 Feb;16(2):224-7. Epub 2010 Jan 17. PMC3070948.
  2. Campbell, JJ, Clark, RA, Watanabe, R, and Kupper, TS. Sézary Syndrome and mycosis fungoides arise from distinct T cell subsets: a biologic rationale for their distinct clinical behaviors.  Blood. 2010 Aug 5;116(5):767-771. Epub 2010 May 18. PMC2918332.
  3. Clark, RA, Watanabe R, Jeatgue JE, Schlapbach C, Tawa MC, Adams N, Dorosario AA, Chaney KS, LeBoeuf NR, Carter JB, Fisher DC, Kupper TS.  Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab treated CTCL patients.  Science Translational Medicine.  2012 Jan: 4(117).  PMC3373186
  4. Jiang X, Clark RA, Liu L, Wagers A, Fuhlbrigge RC, Kupper, TS.  Skin infection generates non-migratory memory CD8+ T cells providing global skin immunity.  Nature.  2012 Feb 29;483 (7388):227-31.  PMC3437663
  5. Seneschal J, Clark RA, Gehad A, Baecher-Allan C, Kupper TS. Human epidermal langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells.  Immunity.  2012 May 25;36(5):873-84.  PMCID in Process.
  6. Purwar R, Schlapbach C, Xiao Sheng, Kang HS, Elyaman W, Jiang X, Jetten A, Khoury S, Fuhlbrigge RC, Kuchroo V, Clark RA, Kupper TS.  Robust tumor immunity to melanoma mediated by interleukin 9. Nature Medicine.  2012.  Published online July 8, doi:10.1038  PMC3518666
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