RelB-Dependent Stromal Cells Promote T-Cell Leukemogenesis

BACKGROUND: The Rel/NF-kappaB transcription factors are often activated in solid or hematological malignancies. In most cases, NF-kappaB activation is found in malignant cells and results from activation of the canonical NF-kappaB pathway, leading to RelA and/or c-Rel activation. Recently, NF-kappaB activity in inflammatory cells infiltrating solid tumors has been shown to contribute to solid tumor initiation and progression. Noncanonical NF-kappaB activation, which leads to RelB activation, has also been reported in breast carcinoma, prostate cancer, and lymphoid leukemia. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a novel role for RelB in stromal cells that promote T-cell leukemogenesis. RelB deficiency delayed leukemia onset in the TEL-JAK2 transgenic mouse model of human T acute lymphoblastic leukemia. Bone marrow chimeric mouse experiments showed that RelB is not required in the hematopoietic compartment. In contrast, RelB plays a role in radio-resistant stromal cells to accelerate leukemia onset and increase disease severity. CONCLUSIONS/SIGNIFICANCE: The present results are the first to uncover a role for RelB in the crosstalk between non-hematopoietic stromal cells and leukemic cells. Thus, besides its previously reported role intrinsic to specific cancer cells, the noncanonical NF-kappaB pathway may also play a pro-oncogenic role in cancer microenvironmental cells

T cell adhesion and cytolysis of pancreatic cancer cells: a role for E-cadherin in immunotherapy?

Pancreatic cancer is an aggressive and potent disease, which is largely resistant to conventional forms of treatment. However, the discovery of antigens associated with pancreatic cancer cells has recently suggested the possibility that immunotherapy might become a specific and effective therapeutic option. T cells within many epithelia, including those of the pancreas, are known to express the αEβ7-integrin adhesion molecule, CD103. The only characterised ligand for CD103 is E-cadherin, an epithelial adhesion molecule which exhibits reduced expression in pancreatic cancer. In our study, CD103 was found to be expressed only by activated T cells following exposure to tumour necrosis factor beta 1, a factor produced by many cancer cells. Significantly, the expression of this integrin was restricted mainly to class I major histocompatibility complex-restricted CD8+ T cells. The human pancreatic cancer cell line Panc-1 was transfected with human E-cadherin in order to generate E-cadherin negative (wild type) and positive (transfected) sub-lines. Using a sensitive flow cytometric adhesion assay it was found that the expression of both CD103 (on T cells) and E-cadherin (on cancer cells) was essential for efficient adhesion of activated T cells to pancreatic cancer cells. This adhesion process was inhibited by the addition of antibodies specific for CD103, thereby demonstrating the importance of the CD103→E-cadherin interaction for T-cell adhesion. Using a 51Cr-release cytotoxicity assay it was found that CD103 expressing T cells lysed E-cadherin expressing Panc-1 target cells following T cell receptor stimulation; addition of antibodies specific for CD103 significantly reduced this lysis. Furthermore, absence of either CD103 from the T cells or E-cadherin expression from the cancer cells resulted in a significant reduction in cancer cell lysis. Therefore, potentially antigenic pancreatic cancer cells could evade a local anti-cancer immune response in vivo as a consequence of their loss of E-cadherin expression; this phenotypic change may also favour metastasis by reducing homotypic adhesion between adjacent cancer cells. We conclude that effective immunotherapy is likely to require upregulation of E-cadherin expression by pancreatic cancer cells or the development of cytotoxic immune cells that are less dependent on this adhesion molecule for efficient effecter function

Early decrease of interferon-gamma+ and interleukin-2+ T cells during combination treatment with interferon-alpha and ribavirin in patients with chronic hepatitis C.

Early decrease of interferon-gamma+ and interleukin-2+ T cells during combination treatment with interferon-alpha and ribavirin in patients with chronic hepatitis

Thymic epithelial cell-derived interleukin-7 promotes survival of human T-cell acute lymphoblastic leukemia

In normal T-cell development, thymic epithelial cells (TECs) exert an inductive role in migration, survival and maturation of thymocytes through the generation of a local gradient of cytokines and the establishment of adhesive interactions with immature T cells. Interleukin- 7 (IL-7), secreted by thymic stromal cells, has a nonredundant role in regulating the early phases of T-cell dif- ferentiation. Furthermore, it is known that IL-7 promotes survival and induces cell cycle progression of T-cell acute lymphoblastic leukemia (T-ALL) cells in vitro. In this study we analysed the role of IL-7 on T-ALL blast survival with- in the microenvironment generated by T-ALL-TEC interaction. To this aim T-ALL blasts derived from 10 adult patients were cultured with TECs obtained from human normal thymuses. The level of blast apoptosis was measured by annexin V-PI co-staining and flow cytometry. The proliferative response of leukemic cells to TEC inter- action was evaluated by 3H-TdR incorporation at various time intervals of culture. To assess the role of IL-7, lympho-epithelial co-cultures were carried out in the presence of anti-IL-7 or anti IL7-R blocking antibodies and T-ALL blasts were then analysed for the apoptosis level. When T-ALL cells were cultured in the presence of TEC monolayers, the percentage of viable cells were sig- nificantly increased and this protection was sustained with time in culture. In addition, the interaction with TECs induced a considerable proliferative response in T- ALL cells (15-fold the control cells after 7 days of cul- ture). The presence of IL-7 or IL-7R blocking antibodies in lympho-epithelial co-cultures consistently reduced the extent of TEC-mediated protection in T-ALL blasts (70% decrease). These results show that IL-7-IL7-R interplay has the major role in the modulation of T-ALL survival within the microenvironment generated by the T-ALL-TEC interaction