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Structural surfaceomics reveals an AML-specific conformation of integrin β₂ as a CAR T cellular therapy target.

ABSTRACT: Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture 'structural surfaceomics'. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin β₂ as a structurally defined, widely expressed AML-specific target. We develop and characterize recombinant antibodies to this protein conformation and show that chimeric antigen receptor T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.

SUBMITTER: Mandal K

PROVIDER: S-EPMC10663162 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Structural surfaceomics reveals an AML-specific conformation of integrin β<sub>2</sub> as a CAR T cellular therapy target.

Mandal Kamal K Wicaksono Gianina G Yu Clinton C Adams Jarrett J JJ Hoopmann Michael R MR Temple William C WC Izgutdina Adila A Escobar Bonell Patiño BP Gorelik Maryna M Ihling Christian H CH Nix Matthew A MA Naik Akul A Xie William H WH Hübner Juwita J Rollins Lisa A LA Reid Sandy M SM Ramos Emilio E Kasap Corynn C Steri Veronica V Serrano Juan Antonio Camara JAC Salangsang Fernando F Phojanakong Paul P McMillan Melanie M Gavallos Victor V Leavitt Andrew D AD Logan Aaron C AC Rooney Cliona M CM Eyquem Justin J Sinz Andrea A Huang Benjamin J BJ Stieglitz Elliot E Smith Catherine C CC Moritz Robert L RL Sidhu Sachdev S SS Huang Lan L Wiita Arun P AP

Nature cancer 20231030 11

Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface ca ...[more]

PMID: 37904046

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Project description:Finely tuning mechanosensitive membrane proteins holds great potential in precisely controlling inflammatory responses. In addition to macroscopic force, mechanosensitive membrane proteins are reported to be sensitive to micro-nano forces. Integrin β2, for example, might undergo a piconewton scale stretching force in the activation state. High-aspect-ratio nanotopographic structures were found to generate nN-scale biomechanical force. Together with the advantages of uniform and precisely tunable structural parameters, it is fascinating to develop low-aspect-ratio nanotopographic structures to generate micro-nano forces for finely modulating their conformations and the subsequent mechanoimmiune responses. In this study, low-aspect-ratio nanotopographic structures were developed to finely manipulate the conformation of integrin β2. The direct interaction of forces and the model molecule integrin αXβ2 was first performed. It was demonstrated that pressing force could successfully induce conformational compression and deactivation of integrin αXβ2, and approximately 270 to 720 pN may be required to inhibit its conformational extension and activation. Three low-aspect-ratio nanotopographic surfaces (nanohemispheres, nanorods, and nanoholes) with various structural parameters were specially designed to generate the micro-nano forces. It was found that the nanorods and nanohemispheres surfaces induce greater contact pressure at the contact interface between macrophages and nanotopographic structures, particularly after cell adhesion. These higher contact pressures successfully inhibited the conformational extension and activation of integrin β2, suppressing focal adhesion activity and the downstream PI3K-Akt signaling pathway, reducing NF-κB signaling and macrophage inflammatory responses. Our findings suggest that nanotopographic structures can be used to finely tune mechanosensitive membrane protein conformation changes, providing an effective strategy for precisely modulating inflammatory responses.Electronic supplementary materialSupplementary material (primer sequences of target genes in RT-qPCR assay; the results of solvent accessible surface area during equilibrium simulation, the ligplut results of hydrogen bonds, and hydrophobic interactions; the density of different nanotopographic structures; interaction analysis of the downregulated leading genes of "focal adhesion" signaling pathway in nanohemispheres and nanorods groups; and the GSEA results of "Rap 1 signaling pathway" and "regulation of actin cytoskeleton" in different groups) is available in the online version of this article at 10.1007/s12274-023-5550-0.

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Structural surfaceomics reveals an AML-specific conformation of integrin β₂ as a CAR T cellular therapy target.

Publications

Structural surfaceomics reveals an AML-specific conformation of integrin β<sub>2</sub> as a CAR T cellular therapy target.

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Structural surfaceomics reveals an AML-specific conformation of integrin β2 as a CAR T cellular therapy target.

Publications

Structural surfaceomics reveals an AML-specific conformation of integrin β&lt;sub&gt;2&lt;/sub&gt; as a CAR T cellular therapy target.

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OmicsDI is part of the ELIXIR infrastructure

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Structural surfaceomics reveals an AML-specific conformation of integrin β₂ as a CAR T cellular therapy target.

Structural surfaceomics reveals an AML-specific conformation of integrin β<sub>2</sub> as a CAR T cellular therapy target.