Cancer immunotherapy: weak beats strong

of control by elimination of checkpoint regulating proteins is a promising novel tool in cancer therapy. Such therapies are designed to restore the patients' own antitumor immune response, specifically the activity of cytotoxic T-cells (CTLs), which had been mitigated during the processes of tumor immune evasion. Immune checkpoint blockade can be induced by treatment with appropriate antibodies against checkpoint proteins, like e.g. antibodies against programmed death-1 protein (PD1) or its ligand (PD-L1) that disrupt the PD1/PD-L1 immune checkpoint axis [1]. Although such approaches are promising, they are successful only in a limited fraction of patients. Unfortunately, factors that influence therapy response in such approaches are not well understood so far. It has been reported that tumors that express many neo-antigens due to accumulation of frame shift or point mutations are more susceptible to immune checkpoint blockade than tumors lacking this property [2], suggesting that immunogenicity of tumor antigen T-cell epitopes might play an important role for therapy success or failure. For obvious reasons functional studies supporting this conclusion are difficult to perform in humans, and thus require the use of suitable animal models. 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. In WAP-T NP mice, the SV40 transgene additionally encodes a highly immunogenic T-cell epitope, the NP 118-126-epitope within the nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV). While SV40 T-antigen (TAg) expressed in WAP-T tumor mice is only weakly immunogenic in the BALB/c mouse Editorial background, the chimeric T-Ag/NP protein (TAg NP) in WAP-T NP tumor mice is highly immunogenic. Except for this immunological difference, WAP-T and WAP-T NP tumors are histologically and molecularly extremely similar [6]. We asked, whether in comparison to the weakly immunogenic T-cell epitopes of TAg in WAP-T tumor mice the presence of the highly immunogenic NP-epitope in TAg NP influences anti-PD1/PD-L1 antibody therapy response. The …