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.

Immunotherapy of WAP-TNP mice with early stage mammary gland tumors

“…Transgene induction, tumor growth, as well as histological and molecular tumor characteristics have been summarized recently in Bruns et al, 2015 [ 2 ] and 2016 [ 3 ]. In brief, after induction of the WAP-promoter, SV40 early proteins T-Ag, small t, and 17kT are expressed in epithelial cells of the mammary glands, with a peak during lactation around day 7 post partum (pp).…”

“…We used the transgenic WAP-T NP line NP8 and the WAP-T line T1, either containing the BALB/c mouse specific cytotoxic T lymphocyte (CTL) NP-epitope of LCMV within SV40 T-Ag (T-Ag NP in NP8) or not (T-Ag in T1). Tumor development and tumor characteristics are similar for T1 and NP8 mice [ 2 , 3 ].…”

“…CTL activity could be largely restored by treatment of the mice with anti-PD1 antibodies [ 2 ]. Following up this observation we subjected NP8 and T1 tumor mice to immune checkpoint blockade therapy with antibodies against PD1 or its ligand PD-L1 [ 3 ]. While NP8 tumors had fully re-appeared already less than 14 days after therapy, T1 tumor mice showed a significantly prolonged period of tumor regression up to 31 days.…”

“…Indeed, we were able to show that the NP-epitope elicited a fast and strong epitope-specific CTL response, but at the same time also promoted rapid CD8 + T-cell exhaustion. On the other hand, the relatively good efficacy of the anti-PD1/PD-L1 treatment in WAP-T tumor mice supported the idea that tumors expressing weak tumor antigen T-cell epitopes respond much better to immune checkpoint blockade therapy because re-establishing an exhausted status of CTLs against these epitopes will take much longer [ 3 ].…”

Cancer immunotherapy: weak beats strong

“…Using the well characterized and cross-species validated BALB/c mouse based WAP-T models for triple-negative breast cancer [3,4], we assessed the role of tumor antigen T-cell immunogenicity in PD1/PD-L1 immune checkpoint blockade therapy [5]. We compared the response to anti-PD1/PD-L1 antibody therapy in two different lines of tumor mice (WAP-T and WAP-T NP mice, respectively) immunologically differing only in the expression of a single T-cell epitope in their major tumor antigen: WAP-T and WAP-T NP mice contain both as transgene the SV40 early gene region under control of the whey acidic protein (WAP) promoter, which upon induction codes for SV40 early proteins, with T-antigen being the major tumor antigen.…”