Dr. Stephen E. Ullrich
The University of Texas MD Anderson Cancer Center
Department of Immunology
- Mechanisms underlying UV-induced immune suppression
- Immune suppression and immunotherapy of pancreatic cancer
Role of cell migration in UV-induced immune suppression
Ultraviolet (UV) radiation is a major environmental carcinogen and the primary cause of skin cancer, the most prevalent cancer found in humans. UV-irradiation is also immunosuppressive, and UV-induced immunosuppression is a major risk factor for skin cancer induction. None of the energy contained within the UVB wavelengths of sunlight penetrate beyond the skin, so it is unclear how UV exposure induces systemic immune suppression. For years immunologists have recognized that UV-irradiation induces Langerhans cells to leave the skin and migrate to the draining lymph nodes, where they activate immune suppression. A number of years ago, we demonstrated that transferring IL-4 producing NKT cells from UV-irradiated mice into naïve recipients transferred UV-induced immune suppression. How these cells are activated in vivo was not clear, but during the past year we provided data demonstrating that UV-activated Langerhans cells migrate to the lymph node and active NKT cells. Transferring Langerhans cells from the lymph nodes of UV-irradiated mice to naïve animals transfer immune suppression. However, when the Langerhans cells were injected into NKT-deficient mice (CD1d-/- and Ja-18-/-), no immune suppression was noted. NKT cells isolated from the lymph nodes of UV-irradiated mice secreted significantly more IL-4 than NKT cells isolated from non-irradiated controls. These data indicate that UV-exposure activates the migration of Langerhans cells from the skin to the draining lymph nodes, where they induce immune suppression in vivo by activating NKT cells to secrete IL-4. Because we see no migration of Langerhans cells from the skin to the lymph node in platelet activating factor (PAF) receptor-deficient mice, we suspect PAF is a critical signal that triggers Langerhans cell migration, and studies are in progress to investigate its role in cell migration.
A few years ago we provided evidence demonstrating that UV exposure induces dermal mast cells to leave the skin and migrate to the draining lymph nodes, where they mediate immune suppression. In addition to the well-described suppression of cell-mediated immune reactions, UV exposure suppresses antibody formation. UV-irradiation blocks germinal center (GC) formation, antibody secretion and T follicular helper (Tfh) cell function, in part by altering the expression of transcription factors BCL-6 and BLIMP-1.
A role for mast cells in pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal outlook. Approximately 37,000 Americans annually are diagnosed with PDAC, and almost an equal number die each year due to PDAC. PDAC is resistant to most conventional therapies, including immunotherapy. The resistance to immunotherapy is paradoxical. Tumor antigens are found on PDAC cells. Cancer reactive cytotoxic T cells are found in the blood of pancreatic cancer patients. These data indicate that the immune system can recognize antigens on pancreatic cancer cells and mount a cytotoxic T cell response against PDAC. But the dismal survival rates indicate that the immune system is not clearing the cancer. Current thinking suggests that tumor-induced immunosuppression is the reason that immunotherapy is not working, and countering immune suppression may provide a new avenue for treating this disease. In preliminary studies we observed that: 1: Mast cells are found in both human and mouse PDAC. 2: Orthotopic implantation of pancreatic tumor cells into mast cell-deficient mice resulted in decreased tumor growth compared to wild type controls. 3: When mast cell deficient mice were reconstituted with wild type bone marrow derived mast cells, tumor growth was accelerated, however, when mast cells were derived from interleukin (IL)-10-deficient mice, tumor growth was suppressed, indicating that mast cell derived IL-10 is involved. 4: Inhibition of mast cell function facilitates the migration of CD8 positive, interferon-gamma (IFN-γ) positive, granzyme-B positive, T cells to the pancreas, suggesting that mast cells are critical players in establishing the immune suppressive microenvironment found in PDAC. Current efforts are aimed at determining if therapies designed to block mast cell induced immune suppression will increase the efficacy of immunotherapy for pancreatic cancer.
Program in Immunology