Squamous Cell Carcinoma in Transplantation: Dendritic Cell Subsets and Regulatory T Cells in Catastrophic Carcinomatosis

John A. Carucci, M.D., Ph.D.

Cornell University Medical College

Funded in March, 2007: $600000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Are Immune Responses to Squamous Cell Carcinoma Actively Suppressed in Transplant Patients?

Researchers from the Medical College of Cornell and the Rockefeller University  will attempt to determine whether, in patients who receive a transplanted organ, certain of their immune cells actively suppress their immune system from responding to squamous cell carcinoma of the skin, allowing the potentially deadly tumor to rapidly grow. 

Prior to transplantation, patients receive medication to reduce their immune system’s ability to attack the donated organ. This weakened immune response makes transplant recipients highly vulnerable to opportunistic infections.  Additionally, a majority of transplant recipients develop an aggressive form of squamous cell carcinoma of the skin, which is the second most prevalent type of human cancer.  The researchers suspected that the high incidence and aggressiveness of this cancer in transplant patients, often a deadly situation, was due to a reduced ability of their immune cells to conduct vigilant surveillance of potentially harmful agents. Preliminary evidence, though, suggests that this is not the whole story.

Instead, according to the researchers, patients’ innate immune “dendritic cells,” the body’s sentries, may recognize the cancer, but their responses may be suppressed by regulatory”immune T cells that ordinarily prevent immune responses to harmless agents.  The resultant immune tolerance to the cancer would enable its rapid growth.  Researchers will now test this hypothesis by further comparing immune responses to the cancer in transplant and non-transplant patients. Skin biopsies from patients in each of the two cancer groups will be compared to identify: 1) characteristics of the patients’ immune regulatory T cells and dendritic cells; 2) functions of these cells in response to the cancer; and 3) properties of the cancer cell that dendritic cells initially recognize, so that methods could be developed to strengthen that response so that regulatory T cells could not suppress it.

Significance: The findings ultimately may lead to development of potentially life-saving treatment for transplant recipients who develop squamous cell carcinoma, in which immune cells would attack the cancer but not the transplanted organ.

ABSTRACT

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Squamous Cell Carcinoma in Transplantation: Dendritic Cell Subsets and Regulatory T Cells in Catastrophic Carcinomatosis

Squamous cell carcinoma (SCC) of the skin is a significant cause of morbidity and mortality in transplant recipients. We studied SCC in transplant patients and expected to find a lack of inflammatory response indicating that passive immune suppression was responsible for aggressive behavior of SCC in this population. Instead, we found SCC in transplant recipients to be associated with high numbers of T cells, many expressing the foxp3+ protein characteristic of suppressor T cells, and dendritic cells supporting active suppression by these.

We hypothesize that SCC in the setting of organ transplantation is associated with recognition by regulatory T cells and the induction of tolerogenic dendritic cells. This leads to active suppression of anti-SCC immune responses, and allows rapid growth of the tumors. We propose to investigate this through the following aims: (1) Characterization the DC and T cell subsets in SCC in transplant vs. non-transplant patients; (2) Determination of the function of DC and T cell subsets associated with SCC in transplant vs. non-transplant patients; and (3) Identification of SCC or SCC-transplant specific peptides that alter DC and T cell mediated tumor immunity.

INVESTIGATOR BIOGRAPHIES

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John A. Carucci, M.D., Ph.D.

John A. Carucci, M.D., Ph.D., is the Director of Mohs Micrographic and Dermatologic Surgery at Weill Medical College of Cornell. He is an author of the current guidelines of care for skin cancer in transplant recipients (International Transplant Skin Cancer Collaborative, ITSCC). Dr Carucci is currently the Chair of the Skin Cancer Committee for the American Academy of Dermatology and Chair of the Research Committee for ITSCC. Under his direction, the Section of Mohs Micrographic Surgery has grown into a nationally recognized center of excellence for the treatment of aggressive skin cancer.

Dr. Carucci undertook his M.D., and Ph.D. studies in cellular immunology, at SUNY-Health Science Center at Brooklyn. He then completed his Internship at Yale University School of Medicine, Dermatology Residency at New York University, a Sulzburger Research Fellowship at Rockefeller University, and Fellowship in Mohs Microrgraphic and Advanced Dermatologic Surgery at Yale.

Michelle Lowes is an NIH-funded Instructor in Clinical Investigation at the Laboratory for Investigative Dermatology, Rockefeller University. This Laboratory is recognized as a leading center for the study of immunology as it relates to human skin disease. Dr Lowes completed her medical training, dermatology residency and doctoral studies in Australia (M.D., Ph.D.). She has considerable expertise in studying the immunobiology of human inflammatory skin diseases, such as psoriasis, and also in cutaneous malignancy. Dr Lowes has an interest in human skin-derived dendritic cells, particularly from a translational perspective. She has developed and refined techniques required to phenotype, localize, isolate, and study the function of T cells and dendritic cells from diseased human skin.