Differentiation of BCMA-specific induced pluripotent stem cells into rejuvenated CD8αβ+ T cells targeting multiple myeloma.

Autor:	Bae J; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Kitayama S; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Herbert Z; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Daheron L; Harvard Stem Cell Institute, Harvard University, Cambridge, MA., Kurata K; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Keskin DB; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Livak K; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Li S; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA., Tarannum M; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Romee R; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Samur M; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Munshi NC; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Kaneko S; Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan., Ritz J; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA., Anderson KC; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Harvard Medical School, Boston, MA.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Mar 07; Vol. 143 (10), pp. 895-911.
DOI:	10.1182/blood.2023020528
Abstrakt:	Abstract: A major hurdle in adoptive T-cell therapy is cell exhaustion and failure to maintain antitumor responses. Here, we introduce an induced pluripotent stem cell (iPSC) strategy for reprogramming and revitalizing precursor exhausted B-cell maturation antigen (BCMA)-specific T cells to effectively target multiple myeloma (MM). Heteroclitic BCMA72-80 (YLMFLLRKI)-specific CD8+ memory cytotoxic T lymphocytes (CTL) were epigenetically reprogrammed to a pluripotent state, developed into hematopoietic progenitor cells (CD34+ CD43+/CD14- CD235a-), differentiated into the T-cell lineage and evaluated for their polyfunctional activities against MM. The final T-cell products demonstrated (1) mature CD8αβ+ memory phenotype, (2) high expression of activation or costimulatory molecules (CD38, CD28, and 41BB), (3) no expression of immune checkpoint and senescence markers (CTLA4, PD1, LAG3, and TIM3; CD57), and (4) robust proliferation and polyfunctional immune responses to MM. The BCMA-specific iPSC-T cells possessed a single T-cell receptor clonotype with cognate BCMA peptide recognition and specificity for targeting MM. RNA sequencing analyses revealed distinct genome-wide shifts and a distinctive transcriptional profile in selected iPSC clones, which can develop CD8αβ+ memory T cells. This includes a repertoire of gene regulators promoting T-cell lineage development, memory CTL activation, and immune response regulation (LCK, IL7R, 4-1BB, TRAIL, GZMB, FOXF1, and ITGA1). This study highlights the potential application of iPSC technology to an adaptive T-cell therapy protocol and identifies specific transcriptional patterns that could serve as a biomarker for selection of suitable iPSC clones for the successful development of antigen-specific CD8αβ+ memory T cells to improve the outcome in patients with MM. (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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