title: Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice.
abstract: When compared with vascular cells in normal tissues, pericytes and vascular endothelial cells (VEC) in tumor blood vessels exhibit altered morphology and epigenetic programming that leads to the expression of unique antigens that allow for differential recognition by CD8+T cells. We have previously shown that the Notch antagonist delta-like homolog 1 (DLK1) is a tumor pericyte-associated antigen expressed in setting of melanoma and a range of carcinomas. In this report, we show that therapeutic vaccination against DLK1 in murine models results in slowed tumor growth, but also to the compensatory expression of the DLK1 homolog, DLK2, by tumor-associated pericytes. Vaccines targeting both DLK1 and DLK2 resulted in superior antitumor benefits in association with improved activation and recruitment of antigen-specific Type 1 CD8+T cells, reduced presence of myeloid-derived suppressive cells, T regulatory cell and tumor vascular normalization. The antitumor efficacy of vaccines coordinately targeting DLK1 and DLK2 was further improved by inclusion of PD-L1 blockade, thus defining a combination immunotherapy theoretically suitable for the treatment of a broad range of solid (vascularized) cancers.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine , Pittsburgh, PA, USA.
authors.forename: Kellsye Paula L
authors.initials: KP
authors.lastname: Fabian
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine , Pittsburgh, PA, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Chi-Sabins
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine , Pittsburgh, PA, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Taylor
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine , Pittsburgh, PA, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Fecek
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine , Pittsburgh, PA, USA.
authors.forename: Aliyah
authors.initials: A
authors.lastname: Weinstein
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
keywords: CD8+ T cells; DC; immunotherapy; pericyte; tumor; vaccine; vascular endothelial cell; vascular normalization