Machine Learning-Directed Conversion of Glioblastoma Cells to Dendritic Cell-Like Antigen-Presenting Cells as Cancer Immunotherapy.

Autor:	Liu T; Division of Neuro-Oncology, Department of Neurological Surgery, University of Southern California Keck School of Medicine, Los Angeles, California.; USC Brain Tumor Center, University of Southern California Keck School of Medicine, Los Angeles, California., Jin D; University of Florida College of Medicine, Gainesville, Florida., Le SB; Division of Neuro-Oncology, Department of Neurological Surgery, University of Southern California Keck School of Medicine, Los Angeles, California.; USC Brain Tumor Center, University of Southern California Keck School of Medicine, Los Angeles, California., Chen D; Division of Neuro-Oncology, Department of Neurological Surgery, University of Southern California Keck School of Medicine, Los Angeles, California.; USC Brain Tumor Center, University of Southern California Keck School of Medicine, Los Angeles, California., Sebastian M; University of Florida College of Medicine, Gainesville, Florida., Riva A; University of Florida College of Medicine, Gainesville, Florida., Liu R; University of Florida College of Medicine, Gainesville, Florida., Tran DD; Division of Neuro-Oncology, Department of Neurological Surgery, University of Southern California Keck School of Medicine, Los Angeles, California.; Department of Neurology, University of Southern California Keck School of Medicine, Los Angeles, California.; USC Brain Tumor Center, University of Southern California Keck School of Medicine, Los Angeles, California.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2024 Oct 01; Vol. 12 (10), pp. 1340-1360.
DOI:	10.1158/2326-6066.CIR-23-0721
Abstrakt:	Immunotherapy has limited efficacy in glioblastoma (GBM) due to the blood-brain barrier and the immunosuppressed or "cold" tumor microenvironment (TME) of GBM, which is dominated by immune-inhibitory cells and depleted of CTL and dendritic cells (DC). Here, we report the development and application of a machine learning precision method to identify cell fate determinants (CFD) that specifically reprogram GBM cells into induced antigen-presenting cells with DC-like functions (iDC-APC). In murine GBM models, iDC-APCs acquired DC-like morphology, regulatory gene expression profile, and functions comparable to natural DCs. Among these acquired functions were phagocytosis, direct presentation of endogenous antigens, and cross-presentation of exogenous antigens. The latter endowed the iDC-APCs with the ability to prime naïve CD8+ CTLs, a hallmark DC function critical for antitumor immunity. Intratumor iDC-APCs reduced tumor growth and improved survival only in immunocompetent animals, which coincided with extensive infiltration of CD4+ T cells and activated CD8+ CTLs in the TME. The reactivated TME synergized with an intratumor soluble PD1 decoy immunotherapy and a DC-based GBM vaccine, resulting in robust killing of highly resistant GBM cells by tumor-specific CD8+ CTLs and significantly extended survival. Lastly, we defined a unique CFD combination specifically for the human GBM to iDC-APC conversion of both glioma stem-like cells and non-stem-like cell GBM cells, confirming the clinical utility of a computationally directed, tumor-specific conversion immunotherapy for GBM and potentially other solid tumors. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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