Deregulation of SOCS5 suppresses dendritic cell function in chronic lymphocytic leukemia

Autor(es)

Toniolo, Patricia A. ; Liu, Suhu ; Yeh, Jennifer E. ; Ye, Darwin Q. ; Barbuto, Jose Alexandre M. ; Frank, David A.

• Tipo de documento: Artigo Científico
• Fonte: ONCOTARGET; v. 7, n. 29, p. 46301-46314, JUL 19 2016.
• Citações Web of Science: 8

Resumo

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-4Ra 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. (AU)

• Processo FAPESP: 12/01623-9 - Pirimetamina na imunoterapia antitumoral: relação entre a inibição de STAT3 e a indução de células dendríticas inflamatórias
• Beneficiário: Patricia Argenta Toniolo
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 10/15312-0 - Suppressors of cytokines signaling (SOCS) na modulação funcional de células dendríticas derivadas de pacientes com câncer
• Beneficiário: Patricia Argenta Toniolo
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 09/54599-5 - Células dendríticas: elementos integrados do sistema imune - enfoque aplicado
• Beneficiário: Jose Alexandre Marzagão Barbuto
• Linha de fomento: Auxílio à Pesquisa - Temático