Tumor pericyte-associated antigens DLK1 and DLK2 as targets for cancer immunotherapy (VAC13P.1131)

Abstract

Abstract The vasculature of solid tumors is essential for their progressive growth and is abnormal structurally and functionally. Notably, pericytes and vascular endothelial cells (VEC) in tumors exhibit altered epigenetic programming and express antigens that allow for their differential recognition (vs. vascular cells in normal tissues) by therapeutic T cells. Therefore, targeting immune reactivity against these antigens via specific vaccination may be a viable therapeutic approach against solid tumors. We show that pericytes isolated from human and murine renal cell carcinoma (RCC) and melanoma overexpress the antigens Delta-like homologue 1 (DLK1) and its homologue DLK2. Using recombinant lentiviruses and adenoviruses encoding full-length murine DLK1 and DLK2 proteins, we show that coordinate genetic vaccination against these two antigens leads to superior therapeutic inhibition of RENCA and B16 tumor growth in vivo when compared to tumor-bearing mice vaccinated against either DLK1 or DLK2 alone. The coordinate vaccination protocol also resulted in the activation of DLK1- and DLK2-specific CD8+ T cells, recruitment of T cells into the tumor microenvironment, loss of DLK1 and DLK2 expressing pericytes and structural normalization of tumor-associated blood vessels. We conclude that specific vaccination against (oncofetal) DLK1 and/or DLK2 may represent an effective strategy for the treatment of vascularized, solid forms of cancer (including RCC and melanoma, among others).