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T-cell epitope strength in WAP-T mouse mammary carcinomas is an important
determinant in PD1/PD-L1 immune checkpoint blockade therapy
#MMPMID27579535
Bruns M
; Wanger J
; Schumacher U
; Deppert W
Oncotarget
2016[Oct]; 7
(40
): 64543-64559
PMID27579535
show ga
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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