Therapeutic DC vaccination against the vascular antigen DLK1 effectively treats primary triple-negative breast cancer and prevents metastasis.

Despite improved treatment options for triple-negative breast cancer (TNBC) patients including immune checkpoint blockade (ICB) alongside chemotherapy, clinical prognosis for these individuals remains poor with regard to disease recurrence and tumor metastasis. Novel interventional approaches are desperately needed. A promising immunotherapeutic strategy involves the selective targeting of tumor blood vessels to coordinately limit tumor growth and metastasis. Here, we describe the use of a dendritic cell (DC) vaccine to elicit immunity against the conserved tumor blood vessel antigen (TBVA) DLK1, which is upregulated and expressed by abluminal pericytes in the tumor microenvironment (TME) of TNBC patients. Our results demonstrate the ability of therapeutic DC vaccination to safely provoke anti-angiogenic T cell activation and recruitment into the TME, resulting in significant reduction in primary and metastatic tumor burden in translational TNBC mouse models when co-administered with anti-PD1 ICB. Interestingly, vaccines targeting DLK1 also promote spreading of polyclonal T cell responses against TNBC antigens that likely fortified tumor control in treated mice. These findings support the anti-tumor efficacy of DC-based vaccines targeting DLK1 and the translation of this approach as a novel treatment strategy for patients with TNBC.