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To increase cancer immunotherapy success, PD-1 blockade must be combined with rationally selected treatments. Here, we examined, in a poorly immunogenic mouse breast cancer model, the potential of antibody-based immunomodulation and conventional anticancer treatments to collaborate with anti–PD-1 treatment. One requirement to improve anti-PD-1–mediated tumor control was to promote tumor-specific cytotoxic T-cell (CTL) priming, which was achieved by stimulating the CD137 costimulatory receptor. A second requirement was to overrule PD-1–unrelated mechanisms of CTL suppression in the tumor microenvironment (TME). This was achieved by radiotherapy and cisplatin treatment. In the context of CD137/PD-1–targeting immunotherapy, radiotherapy allowed for tumor elimination by altering the TME, rather than intrinsic CTL functionality. Combining this radioimmunotherapy regimen with low-dose cisplatin improved CTL-dependent regression of a contralateral tumor outside the radiation field. Thus, systemic tumor control may be achieved by combining immunotherapy protocols that promote T-cell priming with (chemo)radiation protocols that permit CTL activity in both the irradiated tumor and (occult) metastases.

Cisplatin modestly reduces the RIT-induced increase in CD8:CD4 T cell ratio and enhances (R)IT-medated control of non-irradiated tumors.

Identification of an AT-3 tumor-specific (CD8) T cell epitope, and targeting either Ly6G or CSF1R does not improve RIT-mediated control of non-irradiated tumor.

Expression of the immunotherapy targets CD137 and PD-1 in AT-3 tumor-bearing mice.

Depletion of effector phenotype T cells from the circulation following RIT combined with FTY720 treatment.

Individual tumor size following radio-immunotherapy delivered as one dose or in 3 x 8 Gy fractions.