Suboptimal T-cell Therapy Drives a Tumor Cell Mutator Phenotype That Promotes Escape from First-Line Treatment

Laura Evgin, Amanda L. Huff, Timothy Kottke, Jill Thompson, Amy M. Molan, Christopher B. Driscoll, Matthew Schuelke, Kevin G. Shim, Phonphimon Wongthida, Elizabeth J. Ilett, Karen Kaluza Smith, Reuben S. Harris, Matt Coffey, Jose S Pulido, Hardev Pandha, Peter J. Selby, Kevin J. Harrington, Alan Melcher, Richard Geoffrey Vile

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Antitumor T-cell responses raised by first-line therapies such as chemotherapy, radiation, tumor cell vaccines, and viroimmunotherapy tend to be weak, both quantitatively (low frequency) and qualitatively (low affinity). We show here that T cells that recognize tumor-associated antigens can directly kill tumor cells if used at high effector-to-target ratios. However, when these tumor-reactive T cells were present at suboptimal ratios, direct T-cell–mediated tumor cell killing was reduced and the ability of tumor cells to evolve away from a coapplied therapy (oncolytic or suicide gene therapy) was promoted. This T-cell–mediated increase in therapeutic resistance was associated with C to T transition mutations that are characteristic of APOBEC3 cytosine deaminase activity and was induced through a TNFa and protein kinase C–dependent pathway. Short hairpin RNA inhibition of endogenous APOBEC3 reduced rates of tumor escape from oncolytic virus or suicide gene therapy to those seen in the absence of antitumor T-cell coculture. Conversely, overexpression of human APOBEC3B in tumor cells enhanced escape from suicide gene therapy and oncolytic virus therapy both in vitro and in vivo. Our data suggest that weak affinity or low frequency T-cell responses against tumor antigens may contribute to the ability of tumor cells to evolve away from first-line therapies. We conclude that immunotherapies need to be optimized as early as possible so that, if they do not kill the tumor completely, they do not promote treatment resistance.

Original languageEnglish (US)
Pages (from-to)828-840
Number of pages13
JournalCancer Immunology Research
Volume7
Issue number5
DOIs
StatePublished - May 1 2019

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Cell- and Tissue-Based Therapy
T-Lymphocytes
Phenotype
Neoplasms
Genetic Therapy
Suicide
Aptitude
Neoplasm Antigens
Therapeutics
Oncolytic Virotherapy
Cytosine Deaminase
Oncolytic Viruses
Tumor Escape
Cancer Vaccines
Coculture Techniques
Drive
Immunotherapy
Protein Kinases
Small Interfering RNA
Radiation

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Suboptimal T-cell Therapy Drives a Tumor Cell Mutator Phenotype That Promotes Escape from First-Line Treatment. / Evgin, Laura; Huff, Amanda L.; Kottke, Timothy; Thompson, Jill; Molan, Amy M.; Driscoll, Christopher B.; Schuelke, Matthew; Shim, Kevin G.; Wongthida, Phonphimon; Ilett, Elizabeth J.; Smith, Karen Kaluza; Harris, Reuben S.; Coffey, Matt; Pulido, Jose S; Pandha, Hardev; Selby, Peter J.; Harrington, Kevin J.; Melcher, Alan; Vile, Richard Geoffrey.

In: Cancer Immunology Research, Vol. 7, No. 5, 01.05.2019, p. 828-840.

Research output: Contribution to journalArticle

Evgin, L, Huff, AL, Kottke, T, Thompson, J, Molan, AM, Driscoll, CB, Schuelke, M, Shim, KG, Wongthida, P, Ilett, EJ, Smith, KK, Harris, RS, Coffey, M, Pulido, JS, Pandha, H, Selby, PJ, Harrington, KJ, Melcher, A & Vile, RG 2019, 'Suboptimal T-cell Therapy Drives a Tumor Cell Mutator Phenotype That Promotes Escape from First-Line Treatment', Cancer Immunology Research, vol. 7, no. 5, pp. 828-840. https://doi.org/10.1158/2326-6066.CIR-18-0013
Evgin, Laura ; Huff, Amanda L. ; Kottke, Timothy ; Thompson, Jill ; Molan, Amy M. ; Driscoll, Christopher B. ; Schuelke, Matthew ; Shim, Kevin G. ; Wongthida, Phonphimon ; Ilett, Elizabeth J. ; Smith, Karen Kaluza ; Harris, Reuben S. ; Coffey, Matt ; Pulido, Jose S ; Pandha, Hardev ; Selby, Peter J. ; Harrington, Kevin J. ; Melcher, Alan ; Vile, Richard Geoffrey. / Suboptimal T-cell Therapy Drives a Tumor Cell Mutator Phenotype That Promotes Escape from First-Line Treatment. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 5. pp. 828-840.
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AU - Evgin, Laura

AU - Huff, Amanda L.

AU - Kottke, Timothy

AU - Thompson, Jill

AU - Molan, Amy M.

AU - Driscoll, Christopher B.

AU - Schuelke, Matthew

AU - Shim, Kevin G.

AU - Wongthida, Phonphimon

AU - Ilett, Elizabeth J.

AU - Smith, Karen Kaluza

AU - Harris, Reuben S.

AU - Coffey, Matt

AU - Pulido, Jose S

AU - Pandha, Hardev

AU - Selby, Peter J.

AU - Harrington, Kevin J.

AU - Melcher, Alan

AU - Vile, Richard Geoffrey

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