Oncotarget

Priority Research Papers:

T-cell epitope strength in WAP-T mouse mammary carcinomas is an important determinant in PD1/PD-L1 immune checkpoint blockade therapy

Michael Bruns, Jara Wanger, Udo Schumacher and Wolfgang Deppert _

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Oncotarget. 2016; 7:64543-64559. https://doi.org/10.18632/oncotarget.11620

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Abstract

Michael Bruns1, Jara Wanger1,4, Udo Schumacher2 and Wolfgang Deppert1,3

1 Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Hamburg, Germany

2 Institute for Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf (UKE), University of Hamburg, Hamburg, Germany

3 Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), University of Hamburg, Hamburg, Germany

4 Woldsenweg, Hamburg, Germany

Correspondence to:

Wolfgang Deppert, email:

Keywords: transgenic breast cancer mouse model, SV40 T-antigen, LCMV NP T-cell epitope, CTL response, differential response to immune checkpoint blockade therapy

Received: July 01, 2016 Accepted: August 21, 2016 Published: August 25, 2016

Abstract

Using the SV40 transgenic WAP-T/WAP-TNP mouse models for mammary carcinomas, we compared the response to immune checkpoint blockade therapy in tumor mice expressing either SV40 T-antigen containing the LCMV NP-epitope (T-AgNP in WAP-TNP mice), or the unmodified T-antigen (T-Ag in WAP-T mice). Specifically, we asked, whether the presence of the highly immunogenic NP-epitope in T-AgNP influences this response in comparison to the weakly immunogenic T-cell epitopes of T-Ag in WAP-T tumor mice. Treatment of WAP-TNP tumor mice with either anti-PD1 or anti-PD-L1 antibodies led to tumor regression, with anti-PD-L1 treatment being more effective. However, tumors had fully re-appeared after 21 days, indicating that CTL exhaustion had been rapidly re-established. Surprisingly, the same treatment applied to WAP-T tumor mice resulted in a significantly prolonged period of tumor regression. We provide evidence that in contrast to the weak antigenic stimuli exerted by T-cell epitopes of T-Ag, the strong antigenic stimulus of the NP-epitope in T-AgNP has a dual effect: (i) a rapid generation of active NP-specific CTLs, accompanied (ii) by accelerated CTL exhaustion. Our data support the hypothesis that the immunogenicity of tumor antigen T-cell epitopes strongly influences the success of immune checkpoint blockade therapy.


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