Pyrimethamine in cancer immunotherapy: relationship between STAT3 inhibition and inflammatory dendritic cells induction

• Grant number: 12/01623-9
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: April 15, 2012
• End date: April 14, 2013
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Jose Alexandre Marzagão Barbuto
• Grantee: Patricia Argenta Toniolo
• Supervisor: David A. Frank
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 10/15312-0 - Suppressors of cytokines signaling (SOCS) in the functional modulation of dendritic cells derived from patients with cancer, BP.DR

Abstract

One of the main mechanisms of tumor escape is manifested in the inability of dendritic cells (DC) to induce an effective antitumor immune response. This phenomenon may involve defects in the differentiation, maturation and function of these cells. It is known that these processes are coordinated by different cytokines whose signaling involves the Jak/STAT pathway. Since the STAT proteins, especially STAT3, are involved both in cancer pathogenesis and DC activation, these proteins are good candidates for investigation in the functional deviations observed in DC from cancer patients. Tumor-induced STAT3 generates an immunosuppressive microenvironment and, therefore, has become a promising target for cancer therapy. Based on that, a clinical trial is currently ongoing, investigating the effects of an inhibitor of STAT3 (the antiparasitic drug, pyrimethamine) in chronic lymphocytic leukemia (CLL) patients. In this setting, we intend to evaluate whether the drug is also able to increase DC immunogenicity. For this, the effects of in vitro treatment with this drug will be analyzed in monocyte-derived DC from healthy donors and then correlated with those obtained with monocytes and DC from CLL patients (submitted, or not, to the treatment with the drug). The consequences of this treatment on phenotype, cytokine production, cytokine receptors expression and the DC ability to stimulate T lymphocytes will be evaluated together with the activation state of the Jak/STAT signaling pathway in the cells. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

TONIOLO, PATRICIA A.; LIU, SUHU; YEH, JENNIFER E.; YE, DARWIN Q.; BARBUTO, JOSE ALEXANDRE M.; FRANK, DAVID A.. Deregulation of SOCS5 suppresses dendritic cell function in chronic lymphocytic leukemia. ONCOTARGET, v. 7, n. 29, p. 46301-46314, JUL 19 2016. (10/15312-0, 12/01623-9, 09/54599-5)

TONIOLO, PATRICIA A.; LIU, SUHU; YEH, JENNIFER E.; MORAES-VIEIRA, PEDRO M.; WALKER, SARAH R.; VAFAIZADEH, VIDA; BARBUTO, JOSE ALEXANDRE M.; FRANK, DAVID A.. Inhibiting STAT5 by the BET Bromodomain Inhibitor JQ1 Disrupts Human Dendritic Cell Maturation. JOURNAL OF IMMUNOLOGY, v. 194, n. 7, p. 3180-3190, APR 1 2015. (12/01623-9, 09/54599-5)