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Related Concept Videos

T Cell Activation and Clonal Selection01:22

T Cell Activation and Clonal Selection

693
T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
693

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Ectopic PU.1 Expression Provides Chimeric Antigen Receptor (CAR) T Cells with Innate Cell Capacities Including IFN-β

Dennis Christoph Harrer1,2, Matthias Eder2, Markus Barden2

  • 1Department of Hematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, Germany.

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Introducing PU.1 into chimeric antigen receptor (CAR) T cells for cancer therapy unexpectedly reduced their effectiveness. This transcription factor impaired CAR T cell function, proliferation, and persistence, hindering tumor control.

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CART celltranscription factor

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Area of Science:

  • Immunology
  • Cell Biology
  • Oncology

Background:

  • Chimeric antigen receptor (CAR) T cell therapy is highly effective against B cell malignancies.
  • Limited efficacy of CAR T cell therapy in solid tumors is attributed to insufficient T cell activation.
  • The transcription factor PU.1 regulates innate cell function and was investigated for its potential to enhance CAR T cell activation.

Purpose of the Study:

  • To investigate the effect of ectopic PU.1 expression on CAR T cell functionality.
  • To determine if PU.1 can augment pro-inflammatory CAR T cell activation for solid tumor treatment.

Main Methods:

  • Engineered T cells with a CEA-specific CAR and constitutive PU.1 expression.
  • Assessed CAR T cell activation and functionality in vitro under prolonged antigen exposure.
  • Evaluated T cell persistence, proliferation, cytotoxicity, and cytokine production.

Main Results:

  • Ectopic PU.1 upregulated costimulatory receptors (CD40, CD80, CD86, CD70) but did not enhance effector functions.
  • PU.1 expression hampered 4-1BB upregulation, decreased IL-2 production, reduced proliferation, and impaired cytotoxicity.
  • CAR T cells with PU.1 showed reduced persistence and failed to control tumor growth, partly due to IFN-β secretion.

Conclusions:

  • Ectopic PU.1 expression in CAR T cells negatively impacts their effector functions and persistence.
  • PU.1 skews CAR T cell function towards innate-like properties, reducing their anti-tumor efficacy.
  • Targeting PU.1 may be crucial for improving CAR T cell therapy for solid tumors.