Research Project On The Role Of The Innate Immunity In The Pathogenesis Of Pediatric Malignancies And Autoimmune Disease

Project location: Italy, Rome
Project start date: July 2009 - Project end date: January 2010
Project number: 2009-41
Beneficiary: Arcobaleno ONLUS

There is considerable literature evidence indicating that the pathogenesis of a variety of malignancies and autoimmune diseases is conditioned by the innate inflammatory infiltrate in the tumor and inflamed tissues.

Innate inflammatory infiltrate is mainly composed of natural killer cells (NK), and macrophages NK cells contrast tumor growth and viral infections. In this study the researchers will focus on NK cells since their preliminary results suggested that NK cells are barely found in the cancer microenvironment even if cancer would express high level of MICA/B, which is a NK-G2D binder. In addition, NK cells can be detected in pancreas containing MICA/B+ beta cell microenvironment of children with type I diabetes with Coxsackie B4 virus infection.

Based on this information the researchers hypothesize that cancer cells may evade NK cell immunosurveillance by impairing NK cell integrity and function. Conversely, beta cells do not damage NK cells while NK cells do damage beta cell integrity, creating the condition for NK cell based autoimmune response and therefore:

1. Leukemia and cancer cells avoid NK cell recognition by triggering NK cell elimination through an apopototic/necrotic mechanism.
2. The mechanism of NK cell elimination by malignant cells involves the Fcgamma Receptor III (FcγRIII ) expressed on NK cells
3. The interaction between diabetic beta cells and NK cells results in beta cell elimination without affecting NK cell survival and therefore triggering NK cell autoimmunity toward MICA/B+ beta cells.

In this study, utilizing NK cells of healthy children or adults and acute leukemia or pediatric cancer cell lines, the researchers will first demonstrate that leukemia and pediatric cancer cells will trigger NK cell elimination by inducing NK cell apoptosis. Second, they will demonstrate that leukemia and cancer cells will induce NK cell apoptotis through a specific engagement of the NK cell surface, activating molecule, FcγRIII. Third, they will demonstrate that what they have observed in the NK and cancer cell setting would not occur if cancer cells are replaced by insulin, producing beta cells since NK cell/beta cell conjugation will lead to the elimination of beta cell without affecting NK cell viability.

The information obtained in this study will be utilized to define novel immunotherapeutic strategies for improving the management of children and adults with cancer and diabetes mellitus.

This project received a grant from the Nando Peretti Foundation.


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