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Efficient killing of tumor cells by CAR-T cells demands engagement of a larger number of CARs as opposed to TCRs.

Authors
  • Anikeeva, Nadia1
  • Panteleev, Sergey1
  • Mazzanti, Nicholas W1
  • Terai, Mizue2
  • Sato, Takami3
  • Sykulev, Yuri4
  • 1 Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA.
  • 2 Departments of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
  • 3 Departments of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
  • 4 Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA; Departments of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: [email protected]
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry and Molecular Biology
Publication Date
Aug 06, 2021
Pages
101033–101033
Identifiers
DOI: 10.1016/j.jbc.2021.101033
PMID: 34371020
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Although CAR T cells are widely used to treat cancer, efficiency of CAR-T cell cytolytic responses has not been carefully examined. We engineered CAR specific for HMW-MAA (high molecular weight melanoma-associated antigen) and evaluated potency of CD8+ CAR-T cells to release cytolytic granules and to kill tissue-derived melanoma cells, which express different levels of HMW-MAA. CAR T cells efficiently killed melanoma cells expressing high level of HMW-MAA, but not melanoma cells with lower levels of HMW-MAA. The same melanoma cells presenting significantly lower level of stimulatory peptide-MHC ligand were readily lysed by T cells transduced with genes encoding α,β-TCR specific for the peptide-MHC ligand. The data suggest that higher level of targeted molecules is required to engage a larger number of CARs than TCRs to induce efficient cytolytic granule release and destruction of melanoma cells. Understanding the difference in molecular mechanisms controlling activation thresholds of CAR- versus TCR-mediated responses will contribute to improving efficiency of CAR T cells required to eliminate solid tumors presenting low levels of targeted molecules. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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