Prognostic and predictive value of immunological parameters for chemoradioimmunotherapy in patients with pancreatic adenocarcinoma.

BACKGROUND: Chemoradioimmunotherapy of patients with pancreatic adenocarcinoma from the CapRI trial did not show any benefit of interferon-α in addition to a 5-fluorouracil (5FU)-based treatment. The aim of this study was to identify immunological parameters in patients from this trial to be used for predictive and/or prognostic purposes. METHODS: The following methods were used: tumour immunohistology, FACS analyses, cytokine measurement, as well as cytotoxicity and ELIspot. Immunological parameters were correlated with patients' survival using the Kaplan-Meier method. RESULTS: Irrespective of therapy type, high lymphocyte accumulation in tumours and frequencies of NK cells and effector (eff) CD8(+) T cells in peripheral blood of the patients were associated with patients' survival. Amount of CD3(+) and effector-memory CD8(+) blood lymphocytes, expression of CD152 and interleukin (IL)-2 serum level showed a predictive value for chemoradioimmunotherapy. Tumoural accumulation of CD3(+) and CD8(+) cells was predictive for outcome of chemotherapy alone. Besides, we identified the frequencies of CD3(+) lymphocytes, effCD8(+) T cells and NK cells in the peripheral blood of the patients, and IL-10 amount in serum, to be predictive values for 5FU-based chemotherapy. CONCLUSIONS: Immunological parameters, identified in this trial as possible markers, may be of interest in personalized medicine towards the improvement of the treatment and prognosis of pancreatic carcinoma patients.

Reactive oxygen species in cancer biology and anticancer therapy.

Reactive oxygen species (ROS) are a group of highly reactive chemicals under tight control of intracellular antioxidants. The balance in oxidation-antioxidation is essential for maintaining normal cell functions, and any imbalance could lead to a wide range of diseases including cancer. The intracellular level of ROS is generally elevated in cancer cells, revealing a critical role of ROS in the process of carcinogenesis and cancer progression. Conversely, there is also evidence showing that ROS can act as cancer suppressors. This may be due to the varying antioxidant capacities of different cancers. These findings indicate a complex redox state in cancer cells. In this review we summarize the main features of ROS and their functions with respect to cancer initiation, hallmarks of cancer, and signaling in cancer cells. ROS-elevating and ROS-depleting anticancer strategies and their mechanisms are thoroughly discussed. We argue that the rationale for therapy choice depends on a complete understanding of cancer cell redox state, namely, the "redox signaling signature" of cancer.

Interaction of regulatory T cells with antigen-presenting cells in health and disease.

Among antigen-presenting cells (APCs), dendritic cells as well as monocytes acquire immunostimulatory capacity only after appropriate maturation. Therefore, blockade of the maturation/activation results in a steady state or alternatively activated phenotype, which induces tolerance rather than immunity. Functional analyses revealed recently that steady-state dendritic cells and alternatively activated macrophages, respectively, actively induce regulatory T cells (Tregs) in the periphery of the body. Thus, production of Tregs does not rely exclusively on thymic development. Vice versa, Tregs respond to APCs by several means. Recent lines of evidence indicate that Tregs prevent terminal differentiation of subpopulations of APCs or lead to upregulation of surface expression of immunosuppressive molecules. Thus, Tregs foster an environment that further promotes their development. In conclusion, the mutual interaction of Tregs and APCs enables Tregs to sustain their immunosuppressive function(s), which in healthy individuals may be crucial for the maintenance of peripheral tolerance. Since macrophages bridge the innate and the acquired immune system, Tregs are able to gain influence on the innate immune system by interacting with macrophages beyond the mere interaction with effector T cells.

The initial phase of graft-versus-host disease is associated with a decrease of CD4+CD25+ regulatory T cells in the peripheral blood of patients after allogeneic stem cell transplantation.

The mechanisms that induce and control the alloimmune inflammation of graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (allo-SCT) are still incompletely understood. In the murine system, GvHD can be suppressed by CD4(+)CD25(+) regulatory T cells (TREG), which are generally involved in the suppression of inflammatory reactions. A disruption of the homeostasis between TREG and conventional T cells might therefore be associated with the inflammatory reactions of GvHD. We repetitively measured the frequency of TREG in the peripheral blood of 29 patients within the first 71-373 days after allo-SCT and correlated the results with the clinical course. We demonstrate that the initial phase of GvHD is associated with a significant reduction of TREG in the peripheral blood, while at later stages and during intensified immunosuppressive therapy, increased numbers of TREG appear. These results might indicate a pathogenic role for reduced numbers of TREG in the induction of human GvHD.

Hyaluronate-enhanced hematopoiesis: two different receptors trigger the release of interleukin-1beta and interleukin-6 from bone marrow macrophages.

The glycosaminoglycan hyaluronate (HA) is part of the extracellular environment in bone marrow. We show here that HA activates signal transduction cascades important for hemopoiesis. In myeloid and lymphoid long-term bone marrow cultures (LTBMC), treatment with hyaluronidase (HA'ase) results in reduced production of both progenitor and mature cells. Exogeneous HA added to LTBMC had the opposite effect: it enhanced hematopoiesis. The effect of HA is mediated through two different HA receptors on bone marrow macrophage-like cells, one of which is CD44 while the other is unknown. HA induces bone marrow macrophages to secrete IL-1beta (CD44-dependent) and IL-6 (CD44-independent). The two receptors address different signal transduction pathways: CD44 links to a pathway activating p38 protein kinase while the other yet unknown receptor induces Erk activity. There was no difference of the effect of HA and HA'ase on hematopoiesis in LTBMC and on cytokine production by macrophages in CD44-deficient mice compared with wild-type mice, indicating that the CD44 hyaluronate receptor and its signal transduction can be compensated for. Our data suggest a regulatory role for the extracellular matrix component HA in hematopoiesis and show the induction of signal transduction by HA receptors.