title: T-cell epitope strength in WAP-T mouse mammary carcinomas is an important determinant in PD1/PD-L1 immune checkpoint blockade therapy.
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.
authors: Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Hamburg, Germany.
authors: Michael
authors: M
authors: Bruns
authors: Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Hamburg, Germany.|Woldsenweg, Hamburg, Germany.
authors: Jara
authors: J
authors: Wanger
authors: Institute for Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf (UKE), University of Hamburg, Hamburg, Germany.
authors: Udo
authors: U
authors: Schumacher
authors: Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Hamburg, Germany.|Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), University of Hamburg, Hamburg, Germany.
authors: Wolfgang
authors: W
authors: Deppert
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D060890:B7-H1 Antigen / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D007165:Immunosuppression Therapy; D007167:Immunotherapy / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009698:Nucleoproteins / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000952:Antigens, Polyomavirus Transforming; D060890:B7-H1 Antigen; D018984:Epitopes, T-Lymphocyte; D009698:Nucleoproteins; C491383:Pdcd1 protein, mouse; D010446:Peptide Fragments; D061026:Programmed Cell Death 1 Receptor; C094246:nucleoprotein peptide 118-126, lymphocytic choriomeningitis virus
keywords: CTL response; LCMV NP T-cell epitope; SV40 T-antigen; differential response to immune checkpoint blockade therapy; transgenic breast cancer mouse model