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

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 TNFα 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.

• Authors: 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 G Vile
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 7 Issue 5 Pg. 828-840 (05 2019) ISSN: 2326-6074 [Electronic] United States
• PMID: 30940643 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• Minor Histocompatibility Antigens
• Cytidine Deaminase
• Ganciclovir

Topics

• Animals
• Antigens, Neoplasm (genetics, immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Cytidine Deaminase (genetics, immunology)
• Female
• Ganciclovir (therapeutic use)
• Immunotherapy
• Mammalian orthoreovirus 3
• Melanoma, Experimental (genetics, immunology, therapy)
• Mice, Inbred C57BL
• Mice, Transgenic
• Minor Histocompatibility Antigens (genetics, immunology)
• Mutation
• Oncolytic Virotherapy
• Tumor Escape