Description of Research Expertise

The Sgourakis laboratory blends structural approaches, protein engineering, functional studies using patient samples, and computational biology to elucidate the mechanisms by which tumors process intracellular antigens and present a panel of cell-surface biomarkers that can be targeted for personalized cancer therapy.

Our research centers on understanding the structure and function of the human Major Histocompatibility Complex (MHC), with a goal of facilitating cancer immunotherapy and tuning immune responses to address a variety of diseases. The MHC includes a concentrated group of diverse genes that affect vulnerability to numerous health conditions such as autoimmune disorders, infections, and varied illnesses ranging from cancer to schizophrenia. The MHC’s primary components are Class I and Class II molecules. These molecules are crucial in triggering immune responses by presenting antigenic peptide fragments to T cell receptors, thus signaling an aberrant cellular state. A significant portion of our work focuses on understanding how these molecules are assembled intracellularly, and what functions they serve on the cell surface.

MHC-I proteins are extremely polymorphic (>15,000 known allotypes) in the human population. Each allotype displays a unique repertoire of peptide antigens, ensuring species adaptability to emerging pathogens. However, this complexity challenges the development of robust therapeutic approaches that can cover patients of diverse ethnic backgrounds. A long-term research goal of our laboratory is to gain a detailed atomic-level description of the MHC-I antigen loading process, through our structural and biochemical studies of the chaperones Tapasin and TAPBPR. Our findings are leveraged to develop tools for generating libraries of MHC-I reagents that can be used to screen and select antigenic peptides and monitor antigen-specific T cells across donors. We have developed two orthogonal approaches employing i) Engineered molecular chaperones or ii) conformationally stabilized “open” MHC-I proteins, that can be readily applied to enable peptide exchange in vitro. The molecular tools generated by the new approaches are significantly advancing our understanding of MHC-I antigen repertoires in different disease settings.

MHC-I molecules display the intracellular peptidome on the cell surface, serving as a window for T cell immunosurveillance. Using this process, tumor cells also present fragments derived from oncoproteins, however, targeting tumor-associated MHC-I antigens has been challenging. To address existing barriers to clinical translation, we are developing approaches employing engineered MHC-I chaperones to enhance the immunogenicity of classically cold (low T cell infiltration) tumors, such as pediatric neuroblastoma. In a parallel direction, we are designing novel, peptide-focused binding modules targeting tumor-associated pMHC-I antigens for enabling personalized therapeutics using CAR-Ts or Bispecific T cell Engagers (BiTEs).