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Author Notes:

E-mail: lawrence.lamb@ccc.uab.edu (LSL); hspence@emory.edu (HTS)

Conceived and designed the experiments: LSL GYG HTS.

Performed the experiments: JB AD YS AJ.

Analyzed the data: LSL AD HTS.

Contributed reagents/materials/analysis tools: LSL GYG HTS.

Wrote the paper: LSL AD HTS.

We would like to thank Arthur Nienhuis (St. Jude University, Memphis, TN) for the SIV vector system.

Competing Interests: The authors have declared that no competing interests exist.

Subjects:

Research Funding:

This work was supported by grants from CURE Childhood Cancer to HTS.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MULTIDISCIPLINARY SCIENCES
  • MALIGNANT GLIOMA
  • RECOMBINANT INTERLEUKIN-2
  • ADOPTIVE IMMUNOTHERAPY
  • RECURRENT GLIOBLASTOMA
  • IMMUNOGENE THERAPY
  • IMMUNE-RESPONSE
  • LAK CELLS
  • LYMPHOCYTES
  • CANCER
  • RECEPTOR

Engineered Drug Resistant gamma delta T Cells Kill Glioblastoma Cell Lines during a Chemotherapy Challenge: A Strategy for Combining Chemo- and Immunotherapy

Tools:

Journal Title:

PLoS ONE

Volume:

Volume 8, Number 1

Publisher:

, Pages e51805-e51805

Type of Work:

Article | Final Publisher PDF

Abstract:

Classical approaches to immunotherapy that show promise in some malignancies have generally been disappointing when applied to high-grade brain tumors such as glioblastoma multiforme (GBM). We recently showed that ex vivo expanded/activated γδ T cells recognize NKG2D ligands expressed on malignant glioma and are cytotoxic to glioma cell lines and primary GBM explants. In addition, γδ T cells extend survival and slow tumor progression when administered to immunodeficient mice with intracranial human glioma xenografts. We now show that temozolomide (TMZ), a principal chemotherapeutic agent used to treat GBM, increases the expression of stress-associated NKG2D ligands on TMZ-resistant glioma cells, potentially rendering them vulnerable to γδ T cell recognition and lysis. TMZ is also highly toxic to γδ T cells, however, and to overcome this cytotoxic effect γδ T cells were genetically modified using a lentiviral vector encoding the DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) from the O(6)-methylguanine methyltransferase (MGMT) cDNA, which confers resistance to TMZ. Genetic modification of γδ T cells did not alter their phenotype or their cytotoxicity against GBM target cells. Importantly, gene modified γδ T cells showed greater cytotoxicity to two TMZ resistant GBM cell lines, U373TMZ-R and SNB-19TMZ-R cells, in the presence of TMZ than unmodified cells, suggesting that TMZ exposed more receptors for γδ T cell-targeted lysis. Therefore, TMZ resistant γδ T cells can be generated without impairing their anti-tumor functions in the presence of high concentrations of TMZ. These results provide a mechanistic basis for combining chemotherapy and γδ T cell-based drug resistant cellular immunotherapy to treat GBM.

Copyright information:

© 2013 Lamb et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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