What Are the Molecules Involved in Regulatory T-Cells Induction by Dendritic Cells in Cancer?

Dendritic cells (DCs) are essential for the maintenance of homeostasis in the organism, and they do that by modulating lymphocyte priming, expansion, and response patterns according to signals they receive from the environment. The induction of suppressive lymphocytes by DCs is essential to hinder the development of autoimmune diseases but can be reverted against homeostasis when in the context of neoplasia. In this setting, the induction of suppressive or regulatory T cells contributes to the establishment of a state of tolerance towards the tumor, allowing it to grow unchecked by an otherwise functional immune system. Besides affecting its local environment, tumor also has been described as potent sources of anti-inflammatory/suppressive factors, which may act systemically, generating defects in the differentiation and maturation of immune cells, far beyond the immediate vicinity of the tumor mass. Cytokines, as IL-10 and TGF-beta, as well as cell surface molecules like PD-L1 and ICOS seem to be significantly involved in the redirection of DCs towards tolerance induction, and recent data suggest that tumor cells may, indeed, modulate distinct DCs subpopulations through the involvement of these molecules. It is to be expected that the identification of such molecules should provide molecular targets for more effective immunotherapeutic approaches to cancer

Deregulation of SOCS5 suppresses dendritic cell function in chronic lymphocytic leukemia

One cause of morbidity and mortality in chronic lymphocytic leukemia (CLL) is infection, which results from defects in a number of components of the immune system. In particular, dendritic cells (DCs) are functionally defective in patients with CLL. To understand the molecular mechanism for this abnormality, we focused on signal transduction pathways that regulate the function of monocyte-derived dendritic cells (Mo-DCs). Monocytes from CLL patients exhibit high IL-4Rα expression due to the enhanced activation of STAT3. However, IL-4R signaling is decoupled from activation of its downstream mediator STAT6 by enhanced levels of the negative regulator SOCS5. This impairs differentiation of functionally mature DCs leading to decreased expression of HLA-DR and costimulatory molecules, and reduced secretion of pro-inflammatory cytokines in LPS-activated DCs. Moreover, Mo-DCs from CLL patients display a decreased ability to induce pro-inflammatory T-cell responses. IL-10-treatment of monocytes from healthy donors mimics the alteration in signaling observed in CLL patients, through enhanced STAT3-dependent expression of SOCS5. The higher level of SOCS5 inhibits STAT6 activation and leads to defective DC differentiation. These findings indicate that SOCS5 mediates the impaired function of DCs in CLL patients, and has the potential to be a new therapeutic target for reversing cancer-associated immune suppression

Central nervous system metastases from breast carcinoma: a clinical and laboratorial study in 47 patients Metástases do sistema nervoso central por câncer de mama: estudo clínico-laboratorial em 47 pacientes

In this retrospective study, 47 patients with clinical diagnosis of central nervous system metastases of breast cancer were evaluated by computerized tomography (CT), magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination. The patients were divided in 2 groups: 1, without leptomeningeal neoplasm and 2, with leptomeningeal neoplasm. In the group 2, the time interval between the primary disease and the central nervous system metastasis as well as the survival time were shorter than in group 1 (40 and 4.3 months in group 2 versus 57 and 10 months respectively, in group 1). In both groups the most common neurological symptoms and signs were intracranial hypertension and motor deficits. The most sensitive diagnostic methods were CT and MRI in group 1, and the CSF examination in group 2. The use of the tumor markers CEA and CA-15.3 in the routine examination of CSF showed promising results, mainly in leptomeningeal forms.<br>Neste estudo retrospectivo, 47 pacientes com diagnóstico clínico de metástases do sistema nervoso por câncer de mama foram avaliados por tomografia computadorizada (TC), ressonância nuclear magnética (RNM) e por exames do líquido cefalorraqueano (LCR). Os pacientes foram divididos em 2 grupos: 1, sem neoplasia leptomeníngea e 2, com neoplasia leptomeníngea. No grupo 2 o intervalo de tempo entre a doença primária e o comprometimento do sistema nervoso e o tempo de sobrevida foram menores do que no grupo 1 (40 e 4,3 meses no grupo 2 versus 57 e 10 meses respectivamente, no grupo 1). Os sinais e sintomas neurológicos mais frequentes foram hipertensão intracraniana e déficits motores. Os exames mais sensíveis para o diagnóstico foram a TC e RNM no grupo 1 e o exame do LCR no grupo 2. O uso dos marcadores CEA e CA-15.3 na rotina do LCR mostrou resultados promissores, particularmente nas formas leptomeníngeas