NKG2D ligands as molecular targets in immuno-oncology

ZWIRNER, NORBERTO WALTER

Ouro Preto, Minas Gerais

Congreso; XLIII Congress of the Brazilian Society of Immunology; 2018

Sociedad Brasilera de Inmunología (SBI)

A major obstacle for the development of successful immunotherapy strategies for tumor-bearing patients is to restore anti-tumor immunity. Natural killer (NK) cells and cytotoxic CD8 T lymphocytes (CTL) are major cytotoxic and IFN--producing effector cells that eliminate tumor cells, either spontaneously or in response to therapeutic intervention. NK cells recognize tumor cells through an array of activating receptors such as CD16 (that triggers Ab-dependent cell-mediated cytotoxicity -ADCC-) and NKG2D, among others. In humans, NKG2D recognizes eight different ligands (NKG2DL), all of which are expressed mainly in tumor cells and weakly expressed on normal cells. Among them, the MHC class I chain-related protein A (MICA) is the best characterized. Remarkably, tumors developed immune escape strategies that subvert the biological function of NKG2D though proteolytic shedding of MICA, which is released as soluble MICA (sMICA) and exerts immunosuppressive effects. Accordingly, we reasoned that targeting MICA with Ab may trigger ADCC, while simultaneously promote scavenging of sMICA. To produce such Ab, we generated a highly immunogenic chimeric protein (BLS-MICA) consisting of MICA fused to the highly immunogenic lumazine synthase from Brucella spp. (BLS) and used this chimeric protein to immunize mice to investigate if anti-MICA Ab can reinstate tumor immunity. Mice immunized with BLS-MICA and challenged with tumor cells engineered to express MICA displayed a significant delay in tumor growth, and this effect was mediated by Ab against MICA that promoted scavenging of sMICA and induced ADCC. They also displayed higher intra-tumoral macrophages skewed to a M1/pro-inflammatory phenotype and a higher percentage of antigen-experienced CD8+ T cells than mice that received control Ab. Thus, anti-MICA Ab can reinstate anti-tumor immunity and the chimeric protein BLS-MICA constitutes a promising biotechnological approach for cancer patients.