Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion.

التفاصيل البيبلوغرافية
العنوان:	Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion.
المؤلفون:	Sun, Yi, Florio, Tyler J., Gupta, Sagar, Young, Michael C., Marshall, Quinlen F., Garfinkle, Samuel E., Papadaki, Georgia F., Truong, Hau V., Mycek, Emily, Li, Peiyao, Farrel, Alvin, Church, Nicole L., Jabar, Shereen, Beasley, Matthew D., Kiefel, Ben R., Yarmarkovich, Mark, Mallik, Leena, Maris, John M., Sgourakis, Nikolaos G.
المصدر:	Science Immunology; 2023, Vol. 8 Issue 90, p1-14, 14p
مصطلحات موضوعية:	T cell receptors, CHIMERIC antigen receptors, IMMUNE recognition, HLA histocompatibility antigens, MAJOR histocompatibility complex, TUMOR antigens
مستخلص:	Peptide-centric chimeric antigen receptors (PC-CARs) recognize oncoprotein epitopes displayed by cell-surface human leukocyte antigens (HLAs) and offer a promising strategy for targeted cancer therapy. We have previously developed a PC-CAR targeting a neuroblastoma-associated PHOX2B peptide, leading to robust tumor cell lysis restricted by two common HLA allotypes. Here, we determine the 2.1-angstrom crystal structure of the PC-CAR–PHOX2B–HLA-A24:02–β2m complex, which reveals the basis for antigen-specific recognition through interactions with CAR complementarity-determining regions (CDRs). This PC-CAR adopts a diagonal docking mode, where interactions with both conserved and polymorphic HLA framework residues permit recognition of multiple HLA allotypes from the A9 serological cross-reactive group, covering a combined global population frequency of up to 46.7%. Biochemical binding assays, molecular dynamics simulations, and structural and functional analyses demonstrate that high-affinity PC-CAR recognition of cross-reactive pHLAs necessitates the presentation of a specific peptide backbone, where subtle structural adaptations of the peptide are critical for high-affinity complex formation, and CAR T cell killing. Our results provide a molecular blueprint for engineering CARs with optimal recognition of tumor-associated antigens in the context of different HLAs, while minimizing cross-reactivity with self-epitopes. Editor's summary: T cells engineered with peptide-centric chimeric antigen receptors (PC-CARs) can recognize normally inaccessible tumor antigens once they have been degraded into peptides and presented on the cell surface by major histocompatibility complex (MHC) class I molecules. Sun et al. resolved a 2.1-Å crystal structure of a recently developed PC-CAR (10LH) designed to target an oncoprotein-derived peptide (PHOX2B) up-regulated in neuroblastoma. The structure of 10LH complexed with PHOX2B, HLA-A24:02, and β-2 microglobulin (β2m) reveals that it adopts a diagonal binding mode interacting with both conserved and polymorphic elements of the human leukocyte antigen (HLA) framework, allowing 10LH to recognize various HLA allotypes from the A9 serological cross-reactive group. These insights may aid in the development of future CARs that optimally recognize tumor-derived antigens presented by a variety of HLAs with minimal cross-reactivity. —Seth Thomas Scanlon [ABSTRACT FROM AUTHOR]
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قاعدة البيانات:	Complementary Index

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