Suboptimal T-cell Therapy Drives a Tumor Cell Mutator Phenotype That Promotes Escape from First-Line Treatment.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2019-05-01
Date Accepted
2019-03-27
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.
Citation
Cancer immunology research, 2019, 7 (5), pp. 828 - 840
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
2326-6066
eISSN
2326-6074
Research Team
Targeted Therapy
Translational Immunotherapy
Translational Immunotherapy