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Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions

CD19 chimeric antigen receptor (CAR) T-cells have demonstrated remarkable outcomes in B-cell malignancies. Recently, the novel CD19CAR-T cells incorporated with B-cell costimulatory molecules of CD79A/CD40 demonstrated superior antitumor activity in the B-cell lymphoma model compared with CD28 or 4-...

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Autores principales: Ung, Socheatraksmey, Choochuen, Pongsakorn, Khopanlert, Wannakorn, Maneechai, Kajornkiat, Sangkhathat, Surasak, Terakura, Seitaro, Julamanee, Jakrawadee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729744/
https://www.ncbi.nlm.nih.gov/pubmed/36505428
http://dx.doi.org/10.3389/fimmu.2022.1064339
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author Ung, Socheatraksmey
Choochuen, Pongsakorn
Khopanlert, Wannakorn
Maneechai, Kajornkiat
Sangkhathat, Surasak
Terakura, Seitaro
Julamanee, Jakrawadee
author_facet Ung, Socheatraksmey
Choochuen, Pongsakorn
Khopanlert, Wannakorn
Maneechai, Kajornkiat
Sangkhathat, Surasak
Terakura, Seitaro
Julamanee, Jakrawadee
author_sort Ung, Socheatraksmey
collection PubMed
description CD19 chimeric antigen receptor (CAR) T-cells have demonstrated remarkable outcomes in B-cell malignancies. Recently, the novel CD19CAR-T cells incorporated with B-cell costimulatory molecules of CD79A/CD40 demonstrated superior antitumor activity in the B-cell lymphoma model compared with CD28 or 4-1BB. Here, we investigated the intrinsic transcriptional gene underlying the functional advantage of CD19.79A.40z CAR-T cells following CD19 antigen exposure using transcriptome analysis compared to CD28 or 4-1BB. Notably, CD19.79A.40z CAR-T cells up-regulated genes involved in T-cell activation, T-cell proliferation, and NF-κB signaling, whereas down-regulated genes associated with T-cell exhaustion and apoptosis. Interestingly, CD19.79A.40z CAR- and CD19.BBz CAR-T cells were enriched in almost similar pathways. Furthermore, gene set enrichment analysis demonstrated the enrichment of genes, which were previously identified to correlate with T-cell proliferation, interferon signaling pathway, and naïve and memory T-cell signatures, and down-regulated T-cell exhaustion genes in CD79A/CD40, compared with the T-cell costimulatory domain. The CD19.79A.40z CAR-T cells also up-regulated genes related to glycolysis and fatty acid metabolism, which are necessary to drive T-cell proliferation and differentiation compared with conventional CD19CAR-T cells. Our study provides a comprehensive insight into the understanding of gene signatures that potentiates the superior antitumor functions by CD19CAR-T cells incorporated with the CD79A/CD40 costimulatory domain.
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spelling pubmed-97297442022-12-09 Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions Ung, Socheatraksmey Choochuen, Pongsakorn Khopanlert, Wannakorn Maneechai, Kajornkiat Sangkhathat, Surasak Terakura, Seitaro Julamanee, Jakrawadee Front Immunol Immunology CD19 chimeric antigen receptor (CAR) T-cells have demonstrated remarkable outcomes in B-cell malignancies. Recently, the novel CD19CAR-T cells incorporated with B-cell costimulatory molecules of CD79A/CD40 demonstrated superior antitumor activity in the B-cell lymphoma model compared with CD28 or 4-1BB. Here, we investigated the intrinsic transcriptional gene underlying the functional advantage of CD19.79A.40z CAR-T cells following CD19 antigen exposure using transcriptome analysis compared to CD28 or 4-1BB. Notably, CD19.79A.40z CAR-T cells up-regulated genes involved in T-cell activation, T-cell proliferation, and NF-κB signaling, whereas down-regulated genes associated with T-cell exhaustion and apoptosis. Interestingly, CD19.79A.40z CAR- and CD19.BBz CAR-T cells were enriched in almost similar pathways. Furthermore, gene set enrichment analysis demonstrated the enrichment of genes, which were previously identified to correlate with T-cell proliferation, interferon signaling pathway, and naïve and memory T-cell signatures, and down-regulated T-cell exhaustion genes in CD79A/CD40, compared with the T-cell costimulatory domain. The CD19.79A.40z CAR-T cells also up-regulated genes related to glycolysis and fatty acid metabolism, which are necessary to drive T-cell proliferation and differentiation compared with conventional CD19CAR-T cells. Our study provides a comprehensive insight into the understanding of gene signatures that potentiates the superior antitumor functions by CD19CAR-T cells incorporated with the CD79A/CD40 costimulatory domain. Frontiers Media S.A. 2022-11-24 /pmc/articles/PMC9729744/ /pubmed/36505428 http://dx.doi.org/10.3389/fimmu.2022.1064339 Text en Copyright © 2022 Ung, Choochuen, Khopanlert, Maneechai, Sangkhathat, Terakura and Julamanee https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Ung, Socheatraksmey
Choochuen, Pongsakorn
Khopanlert, Wannakorn
Maneechai, Kajornkiat
Sangkhathat, Surasak
Terakura, Seitaro
Julamanee, Jakrawadee
Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions
title Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions
title_full Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions
title_fullStr Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions
title_full_unstemmed Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions
title_short Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions
title_sort enrichment of t-cell proliferation and memory gene signatures of cd79a/cd40 costimulatory domain potentiates cd19car-t cell functions
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729744/
https://www.ncbi.nlm.nih.gov/pubmed/36505428
http://dx.doi.org/10.3389/fimmu.2022.1064339
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