IFNg-Dependent Interactions between ICAM-1 and LFA-1 counteract prostaglandin E2-mediated inhibition of antitumor CTL responses

Abstract

Tumor-expressed ICAM-1 interaction with LFA-1 on naïve tumor-specific CD8+ T cells not only stabilizes adhesion, but, in the absence of classical B7-mediated costimulation, is also able to provide potent alternative costimulatory signaling resulting in the production of antitumor cytotoxic T lymphocyte (CTL) responses. This study shows that overproduction of prostaglandin (PG) E2 by metastatic murine renal carcinoma (Renca) cells inhibited direct priming of tumor-specific CTL responses in vivo by preventing the IFNgdependent upregulation of ICAM-1 that is vital during the initial priming of naïve CD8+ T cells. The addition of exogenous IFNg during naïve CD8+ T-cell priming abrogated PGE2-mediated suppression, and overexpression of ICAM-1 by tumor cells restored IFNg production and proliferation among PGE2-treated tumor-specific CD8+ T cells; preventing tumor growth in vivo. These findings suggest that novel anticancer immunotherapies, which increase expression of ICAM-1 on tumor cells, could help alleviate PGE2-mediated immunosuppression of antitumor CTL responses.