Reprogramming of Tumor-reactive Tumor-infiltrating Lymphocytes to Human-induced Pluripotent Stem Cells.

Autor:	Islam SMR; Surgery Branch, NCI, NIH, Bethesda, Maryland.; Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland., Maeda T; Surgery Branch, NCI, NIH, Bethesda, Maryland.; Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland., Tamaoki N; Surgery Branch, NCI, NIH, Bethesda, Maryland.; Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland., Good ML; Surgery Branch, NCI, NIH, Bethesda, Maryland.; Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland., Kishton RJ; Surgery Branch, NCI, NIH, Bethesda, Maryland.; Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland., Paria BC; Surgery Branch, NCI, NIH, Bethesda, Maryland., Yu Z; Surgery Branch, NCI, NIH, Bethesda, Maryland., Bosch-Marce M; Surgery Branch, NCI, NIH, Bethesda, Maryland., Bedanova NM; Experimental Pathology Laboratory, NCI, NIH, Bethesda, Maryland., Liu C; Transgenic Core, Division of Intramural Research, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland., Kruhlak MJ; CCR Microscopy Core Facility, NCI, NIH, Bethesda, Maryland., Restifo NP; Surgery Branch, NCI, NIH, Bethesda, Maryland.; Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland., Vizcardo R; Surgery Branch, NCI, NIH, Bethesda, Maryland.; Center for Cell-Based Therapy, NCI, NIH, Bethesda, Maryland.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2023 May 25; Vol. 3 (5), pp. 917-932. Date of Electronic Publication: 2023 May 25 (Print Publication: 2023).
DOI:	10.1158/2767-9764.CRC-22-0265
Abstrakt:	Tumor-infiltrating lymphocytes (TIL) that can recognize and kill tumor cells have curative potential in subsets of patients treated with adoptive cell transfer (ACT). However, lack of TIL therapeutic efficacy in many patients may be due in large part to a paucity of tumor-reactive T cells in TIL and the exhausted and terminally differentiated status of those tumor-reactive T cells. We sought to reprogram exhausted TIL that possess T-cell receptors (TCR) specific for tumor antigens into induced pluripotent stem cells (iPSC) to rejuvenate them for more potent ACT. We first attempted to reprogram tumor neoantigen-specific TIL by αCD3 Ab prestimulation which resulted in failure of establishing tumor-reactive TIL-iPSCs, instead, T cell-derived iPSCs from bystander T cells were established. To selectively activate and enrich tumor-reactive T cells from the heterogenous TIL population, CD8 + PD-1 + 4-1BB + TIL population were isolated after coculture with autologous tumor cells, followed by direct reprogramming into iPSCs. TCR sequencing analysis of the resulting iPSC clones revealed that reprogrammed TIL-iPSCs encoded TCRs that were identical to the pre-identified tumor-reactive TCRs found in minimally cultured TIL. Moreover, reprogrammed TIL-iPSCs contained rare tumor antigen-specific TCRs, which were not detectable by TCR sequencing of the starting cell population. Thus, reprogramming of PD-1 + 4-1BB + TIL after coculture with autologous tumor cells selectively generates tumor antigen-specific TIL-iPSCs, and is a distinctive method to enrich and identify tumor antigen-specific TCRs of low frequency from TIL. Significance: Reprogramming of TIL into iPSC holds great promise for the future treatment of cancer due to their rejuvenated nature and the retention of tumor-specific TCRs. One limitation is the lack of selective and efficient methods for reprogramming tumor-specific T cells from polyclonal TIL. Here we addressed this limitation and present a method to efficiently reprogram TIL into iPSC colonies carrying diverse tumor antigen reactive TCR recombination. (© 2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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