Conference overview: Cancer Immunotherapy and Immunomonitoring (CITIM): moving forward.

The immune system is a critical element involved in the control of tumor development and progression. While professionals have learned how to manipulate the immune system to generate tumor-specific immune responses, cancer immunotherapy has not yet delivered substantial clinical benefits. It has become increasingly clear that tumor-induced abnormalities in the immune system not only hamper tumor immunosurveillance, but also limit the efficacy of cancer immunotherapy. Meanwhile, the results of recent studies allow the belief that one is on the edge of a real breakthrough in this promising direction in cancer therapy. The 2(nd) International Conference 'Cancer Immunotherapy and Immunomonitoring (CITIM)' was the second meeting in Eastern Europe to specifically focus on the issue of immune regulation in the tumor environment, cancer immunotherapy, and immunomonitoring of immunotherapeutic clinical trials. This CITIM Conference held in Budapest, Hungary, was comprised from 12 plenary sessions, Best Abstract Award session, Poster session, and four Keynote lectures. Outstanding presentations and numerous productive discussions summarized the current place of the field and opened new directions for improving monitoring and therapy for patients with cancer.

Cancer immunotherapy and immunomonitoring (CITIM): redefining cancer therapy.

The immune system is a critical element involved in the control of tumor development and progression. While we have learned how to manipulate the immune system to generate tumor-specific immune responses, cancer immunotherapy has not yet delivered substantial clinical benefits. It has become increasingly clear that tumor-induced abnormalities in the immune system not only hamper natural tumor immune surveillance, but also limit the effect of cancer immunotherapy. If the results of recent studies are of any indication, then we are on the verge of a real breakthrough in our understanding of the immunobiology of tumor-host interactions and of ways to manipulate it. This 1(st) International Conference on "Cancer Immunotherapy and Immunomonitoring (CITIM)" was the first meeting in Eastern Europe to specifically focus on the issue of immune regulation in the tumor environment, cancer immunotherapy, and immunomonitoring of immunotherapeutic clinical trials. This CITIM Conference held in Kiev, Ukraine, was comprised from eight plenary sessions and two special selected poster presentation sessions. Selected contributions from the participants of the Conference are presented in this issue of the Journal of Immunotoxicology.

Dinitrosyl-iron triggers apoptosis in Jurkat cells despite overexpression of Bcl-2.

Cells expressing the cytokine-inducible NO synthase are known to trigger apoptosis in neighboring cells. Paramagnetic dinitrosyl nonheme iron complexes (DNIC) were found in tumor tissue about 40 years ago; however, the role of these NO(+)-bearing species is not completely understood. In the human Jurkat leukemia cell line, the application of the model complex DNIC-thiosulfate (50-200 microM) induced apoptosis (defined by phosphatidylserine externalization) in a concentration- and time-dependent manner. In Jurkat cells, the pan-caspase inhibitor, zVADfmk (50 microM), and/or stable transfection of antiapoptotic protein, Bcl-2, was unable to afford protection against DNIC-induced apoptosis. The membrane-impermeable metal chelator, N-methyl-D-glucamine dithiocarbamate (MGD; 200 microM), in the presence of DNIC significantly increased apoptosis, but had no effect on its own. Electron paramagnetic resonance studies showed that MGD led to rapid transformation of the extracellular DNIC into the stable impermeable NO-Fe-MGD complex and to a burst-type release of nitrosonium (NO(+)) equivalents in the extracellular space. These results suggest that in Jurkat cells, DNIC-thiosulfate induces Bcl-2- and caspase-independent apoptosis, which is probably secondary to local nitrosative stress at the cell surface. We hypothesize that the local release of nonheme Fe-NO species by activated macrophages may play a role in the killing of malignant cells that have high Bcl-2 levels.

Influence of adjuvant hormone therapy and chemotherapy on the immune system analysed in the bone marrow of patients with breast cancer.

PURPOSE: Bone marrow is a special compartment for antitumor immunological memory in patients with breastcancer. Until now, the influence of adjuvant systemic therapy on the immune system has only been investigated in peripheral blood and not in bone marrow. In this study, we analyzed the effect of hormone therapy and chemotherapy on the immune activation status in bone marrow. EXPERIMENTAL DESIGN: In 34 patients with breast cancer, bone marrow was aspirated 24 months after primary surgery and adjuvant systemic therapy. The immune system of these patients was compared with that of patients at the time of primary surgery (n = 90). Three-color flow cytometry was used to identify the number and activation state of T cells, natural killer (NK) cells, monocytes/macrophages, and subsets by means of a panel of monoclonal antibodies. RESULTS: The proportion of all T cells was significantly lower in patients after adjuvant systemic therapy than in patients with primary breast cancer or normal healthy donors. Chemotherapy apparently had a particularly suppressive effect on naïve CD4 T cells and, to a lesser extent, on memory CD4 T cells. Hormone therapy apparently had a significant suppressive effect on both naïve and memory CD8 T cells. The numbers of NK cells (CD56) and of monocytes/macrophages (CD14) recovered rapidly after adjuvant chemotherapy. However, subpopulations with potential antitumor reactivity, such as activated NK and NK T cells, were reduced per long term after chemotherapy. CONCLUSIONS: These findings suggest profound and long-lasting negative effects on the bone marrow immune system by present day adjuvant therapy in breast cancer.