Cell identification and analysis of immuno SUPRESSIVE mechanisms of MYELOID-DERIVED suppressor cells

• Grant number: 14/09351-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: August 01, 2014
• End date: January 31, 2015
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Maria Helena Bellini Marumo
• Grantee: Karen Cristina Barbosa Chaves
• Supervisor: Dmitry I. Gabrilovich
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: Wistar Institute, United States
• Associated to the scholarship: 12/12955-2 - Study of modulation of the myeloid-derived suppressor cells metastatic adenocarcinoma after anti-angiogenic therapy, BP.DR

Abstract

Immuno suppressive effect is different for several diseases and involves released growth factors and cytokines depending on tumor context. The tumor microenvironment is orchestrated by different cells that may promote an important immune-evading mechanism. Studies have identified MDSC as potent suppressors of tumor immunity and, therefore, a significant impediment to cancer immunotherapy. MDSC are a heterogenous population undifferentiated composed of two different morphologies and limited expression markers. However, these cells have been detected in diferentes compartments including blood, lymphoid organs and tumor. MDSC expansion and activation are dependent of specific growth factors and cytokines produced by tumor and stroma cells. MDSC-inducers molecules may induce different STAT and JK signalling pathways in MDSC, promoting proliferation, survival, production of soluble factors and may prevent MDSC differentiation into mature cells. The mechanisms of action of MDSC are diverse requiring either cell to cell contact or the release of soluble factors. The most frequent G-MDSC subtype release ROS and RNS that cause alteration of T cells-surface molecules, thereby inhibiting T cell function. M-MDSC mainly produce ARG1 and iNOS involved in the L-arginine depletion as strategy of limiting T cells expansion and function. Although the complexity of conditions that regulate MDSC expansion and the variety of suppressive mechanisms used by MDSC, it is important to understand which mechanisms are involved and may be targeted in individual patients to reduce MDSC-regulated immune suppression. Clinically, MDSC depletion is desirable before initiating immunotherapeutic modalities. In this study, we propose to isolate tissue MDSC, identify the different subtypes of MDSC and analyze antigen-specific and non-specific suppressor effects of MDSC. (AU)