Designed improvement to T-cell immunotherapy by multidimensional single cell profiling.

Autor:	Bandey IN; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas, USA., Adolacion JRT; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas, USA., Romain G; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas, USA., Paniagua MM; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas, USA., An X; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas, USA., Saeedi A; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas, USA., Liadi I; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas, USA., You Z; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas, USA., Rajanayake RB; Department of Biomedical Engineering, University of Houston, Houston, Texas, USA., Hwu P; Department of of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Singh H; Divsion of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Cooper LJ; Divsion of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Ziopharm Oncology, Houston, Texas, USA., Varadarajan N; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas, USA nvaradar@central.uh.edu.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2021 Mar; Vol. 9 (3).
DOI:	10.1136/jitc-2020-001877
Abstrakt:	Background: Adoptive cell therapy based on the infusion of chimeric antigen receptor (CAR) T cells has shown remarkable efficacy for the treatment of hematologic malignancies. The primary mechanism of action of these infused T cells is the direct killing of tumor cells expressing the cognate antigen. However, understanding why only some T cells are capable of killing, and identifying mechanisms that can improve killing has remained elusive. Methods: To identify molecular and cellular mechanisms that can improve T-cell killing, we utilized integrated high-throughput single-cell functional profiling by microscopy, followed by robotic retrieval and transcriptional profiling. Results: With the aid of mathematical modeling we demonstrate that non-killer CAR T cells comprise a heterogeneous population that arise from failure in each of the discrete steps leading to the killing. Differential transcriptional single-cell profiling of killers and non-killers identified CD137 as an inducible costimulatory molecule upregulated on killer T cells. Our single-cell profiling results directly demonstrate that inducible CD137 is feature of killer (and serial killer) T cells and this marks a different subset compared with the CD107a pos (degranulating) subset of CAR T cells. Ligation of the induced CD137 with CD137 ligand (CD137L) leads to younger CD19 CAR T cells with sustained killing and lower exhaustion. We genetically modified CAR T cells to co-express CD137L, in trans, and this lead to a profound improvement in anti-tumor efficacy in leukemia and refractory ovarian cancer models in mice. Conclusions: Broadly, our results illustrate that while non-killer T cells are reflective of population heterogeneity, integrated single-cell profiling can enable identification of mechanisms that can enhance the function/proliferation of killer T cells leading to direct anti-tumor benefit. Competing Interests: Competing interests: LJNC is the CEO of Ziopharm. LJNC and NV are founders of CellChorus. (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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