Construction and characterization of a recombinant vaccinia virus expressing murine intercellular adhesion molecule-1: induction and potentiation of antitumor responses

Abstract

The intercellular adhesion molecule-1 (ICAM-1) has been associated with cellular migration into inflammatory sites and with facilitating interactions between lymphocytes and tumor targets in the pathway of cell-mediated cytotoxicity. More recently, ICAM-1 has become increasingly implicated in the costimulation of T cell functions, such as antigen-dependent T cell proliferation. Previous murine studies have shown that the introduction of the ICAM-1 gene into tumor cells using retroviral vectors led to enhanced antitumor responses. In this study, we report the construction, characterization, and immunological consequences of a recombinant vaccinia virus expressing murine ICAM-1. Vaccinia virus represents an attractive vector for the delivery of molecules such as ICAM-1 due to its wide host range, rapid infection, and functional expression of inserted gene products. The infection of tumor cells with this recombinant virus resulted in the expression of functional ICAM-1. Infected tumors provide accessory or secondary signals to lymphoblasts in vitro, resulting in enhanced cytokine production or alloreactive cytotoxic T lymphocyte (CTL) activity. In vivo, we demonstrated that weakly immunogenic syngeneic tumors, infected with and expressing rV-ICAM-1, were rejected by immunocompetent hosts. Furthermore, immunization with rV-ICAM-1-infected tumors resulted in the rejection of subsequent tumor challenge, providing evidence for recall response and immunological memory. These studies demonstrated the utility of a recombinant vaccinia virus to deliver and efficiently express ICAM-1 molecules on tumor cells for potential gene therapy and recombinant approaches to cancer immunotherapy.