ICAM-1 overexpression counteracts immune-suppression by tumour cell-derived PGE 2 to restore CTL function.

Tumour-infiltrating cytotoxic T lymphocytes (CTLs) play a key role in tumour killing. However, many cancers adopt various strategies to induce immunosuppression. Priming of naive CD8+ T cells to become CTLs occurs via cognate interactions of the T cell receptor (TcR) and CD28 with tumour-derived peptide epitopes expressed on major histocompatibility complex (MHC) class I molecules and CD80/CD86 on T cells and antigen-presenting cells (APCs) respectively. Here we report that, in the absence of CD80/CD86 expression by renal carcinoma (Renca) cells, expression of intercellular adhesion molecule-1 (ICAM-1) by Renca cells provides a potent alternative co-stimulation to a tumour-specific CD8+ T cells causing them to produce interferon gamma (IFN-γ) which is crucial for the further up-regulation of ICAM-1 on tumour cells. We have shown that overexpression of cyclooxygenase-2 (COX-2), by Renca cells (Renca-T3), results in increased levels of prostaglandin (PG) E2 production, which can directly suppress anti-tumour CD8+ T cells resulting in loss of CTL function in vivo and cause metastases to the tumor-draining lymph nodes (TDLNs). Significantly, our data also show that overexpression of ICAM-1 on Renca-T3 cells can counteract the immune-suppressive effect of PGE2 and restore CTL responses.