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 IFNγ-dependent upregulation of ICAM-1 that is vital during the initial priming of naïve CD8⁺ T cells. The addition of exogenous IFNγ during naïve CD8⁺ T-cell priming abrogated PGE₂-mediated suppression, and overexpression of ICAM-1 by tumor cells restored IFNγ 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. Cancer Immunol Res; 4(5); 400–11. ©2016 AACR.