Faculty
Nikolaos Sgourakis, PhD
Associate Professor of Biochemistry and Biophysics
Department: Biochemistry and Biophysics
Graduate Group Affiliations
Contact information
CHOP
9012 Colket Transalational Building
Civic Center Boulevard
Philadelphia, PA 19104
9012 Colket Transalational Building
Civic Center Boulevard
Philadelphia, PA 19104
Office: 267-425-0110
Publications
Education:
undergrad (Ptychion in Biology)
National University of Athens, 2004.
M.Sc. (Bioinformatics)
National University of Athens, 2005.
Ph.D. (Dissertation in Molecular Biophysics)
Rensselaer Polytechnic Institute, 2009.
Permanent linkundergrad (Ptychion in Biology)
National University of Athens, 2004.
M.Sc. (Bioinformatics)
National University of Athens, 2005.
Ph.D. (Dissertation in Molecular Biophysics)
Rensselaer Polytechnic Institute, 2009.
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).
Selected Publications
Gupta S., and Sgourakis N.G.: A structure-guided approach to predict MHC-I restriction of T cell receptors for public antigens. bioarchive June 2024.McShan A.C., Flores-Solis D., Sun Y., Garfinkle S., Young M.C., Toor J., Sgourakis N.G. : Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition Nature Communications 14, December 2023.
Sun Y., Florio T.J., Gupta S., Young M.C., Marshall Q.F., Garfinkle S.E., Papadaki G.F., Truong H.V., Mycek E., Li P., Farrel A., Church N.L., Jabar S., Beasley M.D., Kiefel B.R., Yarmarkovich M., Mallik L., Maris J.M., Sgourakis N.G.: Structural principles of peptide-centric Chimeric Antigen Receptor recognition guide ther- apeutic expansion Science Immunology 8, December 2023.
Yarmarkovich M, Marshall QF, Warrington JM, Premaratne R, Farrel A, Groff D, Li W, di Marco M, Runbeck E, Truong H, Toor JS, Tripathi S, Nguyen S, Shen H, Noel T, Church NL, Weiner A, Kendsersky N, Martinez D, Weisberg R, Christie M, Eisenlohr L, Bosse KR, Dimitrov DS, Stevanovic S, Sgourakis NG, Kiefel BR, Maris JM.: Targeting of intracellular oncoproteins with peptide-centric CARs. Nature 623: 820-827, November 2023.
Gupta S., Nerli S., Kutti Kandi S., Merski G.L., Sgourakis N.G.: HLA3DB: comprehensive annotation of peptide/HLA complexes enables blind structure prediction of T cell epitopes Nature Communications 14(1), October 2023.
Papadaki G.F., Woodward C.H., Young M.C., Winters T.J., Burslem G.M., Sgourakis N.G.: A Chicken Tapasin ortholog can chaperone empty HLA-B37:01 molecules independent of other peptide-loading components Journal of Biological Chemistry 299(10), October 2023.
Sun Y., Young M.C., Woodward C.H., Danon J.N., Truong H.V., Gupta S., Winters T.J., Font-Burgada J. Burslem G.M., Sgourakis N.G.: Universal open MHC-I molecules for rapid peptide loading and enhanced complex stability across HLA allotypes Proc Natl Acad Sci U S A 120(25), June 2023.
Sun Y., Papadaki G.F., Devlin C.A., Young M.C., Woodward C.H., Danon J.N., Truong H.V., Gupta S., Winters T.J., Burslem G.M., Procko E., Sgourakis N.G.: Xeno interactions between MHC-I proteins and molecular chaperones enable ligand ex- change on a broad repertoire of HLA allotypes Science Advances 9, February 2023.
Papadaki G.F., Ani O., Florio T.J., Young M.C., Danon J.N., Sun Y., Dersh D., Sgourakis N.G.: Decoupling peptide binding from T cell receptor recognition with engineered chimeric MHC-I molecules Frontiers in Immunology 14, January 2023.
Hu K., Lee W., Montelione G.T., Sgourakis N.G., Vogeli B.: Computational approaches for interpreting experimental data and understanding protein structure, dynamics and function relationships Frontiers in Molecular Biosciences 9, October 2022.
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