An immunoproteomic approach to characterize the CAR interactome and signalosome.

Autor:	Ramello MC; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Benzaïd I; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Kuenzi BM; Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620, USA., Lienlaf-Moreno M; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Kandell WM; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620, USA., Santiago DN; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.; Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Pabón-Saldaña M; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Darville L; Proteomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Fang B; Proteomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Rix U; Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Yoder S; Molecular Genomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Berglund A; Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Koomen JM; Proteomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.; Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Haura EB; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Abate-Daga D; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. daniel.abatedaga@moffitt.org.; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2019 Feb 12; Vol. 12 (568). Date of Electronic Publication: 2019 Feb 12.
DOI:	10.1126/scisignal.aap9777
Abstrakt:	Adoptive transfer of T cells that express a chimeric antigen receptor (CAR) is an approved immunotherapy that may be curative for some hematological cancers. To better understand the therapeutic mechanism of action, we systematically analyzed CAR signaling in human primary T cells by mass spectrometry. When we compared the interactomes and the signaling pathways activated by distinct CAR-T cells that shared the same antigen-binding domain but differed in their intracellular domains and their in vivo antitumor efficacy, we found that only second-generation CARs induced the expression of a constitutively phosphorylated form of CD3ζ that resembled the endogenous species. This phenomenon was independent of the choice of costimulatory domains, or the hinge/transmembrane region. Rather, it was dependent on the size of the intracellular domains. Moreover, the second-generation design was also associated with stronger phosphorylation of downstream secondary messengers, as evidenced by global phosphoproteome analysis. These results suggest that second-generation CARs can activate additional sources of CD3ζ signaling, and this may contribute to more intense signaling and superior antitumor efficacy that they display compared to third-generation CARs. Moreover, our results provide a deeper understanding of how CARs interact physically and/or functionally with endogenous T cell molecules, which will inform the development of novel optimized immune receptors. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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