Activation of cytotoxic response mediated by polyfunctional natural killer cells and t CD8+ cells induced by Toll-like-receptors agonists in the mycosis fungoides and Sézary syndrome

• Grant number: 14/04865-9
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2015
• End date: February 28, 2017
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: José Antonio Sanches Junior
• Grantee: José Antonio Sanches Junior
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Maria Notomi Sato

Abstract

The most frequent form of cutaneous T cell lymphoma (CTCL), non-Hodgkin's type, is the Mycosis Fungóides (MF) and Sézary Syndrome (SS). In the early stages of CTCL there is a predominant regulatory profile in skin lesions and with disease progression there is a predominance of CD4+ Th2 cells. In parallel, due to tumor escape mechanisms, occurs a declining in the activity of effectors CD8+ T cells and Natural Killer (NK) cells, which are crucial components for antitumor response and controlling of disease progression. The use of innate immunity adjuvants such as Toll-like ligands, mainly those intracellular receptors, has been exploited to potentiate antitumor immunity. The aim of the study is to analyze in mycosis fungoides/Sézary Syndrome the responsiveness of NK cell subtypes and polyfunctional CD8+ T cells to the agonists of Toll-like receptors (TLR) and ligand for STING (stimulator genes for type I IFN). The frequency of regulatory T cells (Foxp3+) will be evaluated. In the mononuclear cells (MNC) from peripheral blood of patients with MF/SS. Therefore, the production of TNF-a, IFN-g, IL-10 and IL-17 by MNC upon TLR 2/7, 7/8 and STING (3', 3'- cGAMP) activation will be assessed. The frequency of NK cells subtypes which express inhibitory receptor (CD94-NKG2A) or activating (NKG2D) and natural cytotoxicity receptors, such as NKp30 and NKp46 as well as CD8+ T cells expressing IFN-g, TNF-±, CD107a will be analyzed upon stimulation with TLR2/7, TLR7/8 and STING ligands. The profile of memory NK cells will also be evaluated in MNCs. The frequency of regulatory T cells (CD3+, CD4+, CD25+, CD45RA, CD127-, CD95, Foxp3+) will be evaluate in non-malignant cells and malignant cells phenotype (CD3+,CD4+, CD5+, CD8-, CD7-,CD26-,CD158k, NKp46, Foxp3+) in the SS cases. The mRNA expression of NK receptor ligands and inhibitory molecules will be analyzed in skin lesions in plaque or tumor stages. The analysis of effect/cytotoxic and regulatory potential is crucial for better understanding the immunopathogenesis and to verify the potential modulator adjuvants as a strategy to enhance the antitumor response in CTCL. (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)

MANFRERE, KELLY C. G.; TORREALBA, MARINA P.; MIYASHIRO, DENIS R.; OLIVEIRA, LUANDA M. S.; DE CARVALHO, GABRIEL C.; LIMA, JOSENILSON F.; BRANCO, ANNA CLAUDIA C. C.; PEREIRA, NTALLI Z.; PEREIRA, JULIANA; SANCHES, JR., JOSE A.; et al. Toll-like receptor agonists partially restore the production of pro-inflammatory cytokines and type I interferon in Sezary syndrome. ONCOTARGET, v. 7, n. 46, p. 74592-74601, NOV 15 2016. (14/04865-9)

TORREALBA, MARINA PASSOS; MANFRERE, KELLY CRISTINA; MIYASHIRO, DENIS R.; LIMA, JOSENILSON F.; OLIVEIRA, LUANA DE M.; PEREIRA, NATALLI Z.; CURY-MARTINS, JADE; PEREIRA, JULIANA; DUARTE, ALBERTO J. S.; SATO, MARIA N.; et al. Chronic activation profile of circulating CD8+T cells in Sezary syndrome. ONCOTARGET, v. 9, n. 3, p. 3497-3506, JAN 9 2018. (14/04865-9)

MANFRERE, KELLY C. G.; TORREALBA, MARINA P.; MIYASHIRO, DENIS R.; PEREIRA, NATALLI Z.; YOSHIKAWA, FABIO S. Y.; OLIVEIRA, LUANA DE M.; CURY-MARTINS, JADE; DUARTE, ALBERTO J. S.; SANCHES, JOSE A.; SATO, MARIA N.. Profile of differentially expressed Toll-like receptor signaling genes in the natural killer cells of patients with Sezary syndrome. ONCOTARGET, v. 8, n. 54, p. 92183-92194, NOV 3 2017. (14/04865-9)