Expression and shedding of ICAM‐1 in bladder cancer and its immunotherapy

Intercellular adhesion molecule‐1 (ICAM‐1) is one of 3 major ligands for the β2 integrin leucocyte function‐associated antigen‐ I (LFA‐1). Several reports have emerged describing soluble forms of ICAM‐1 in association with normal and pathological states (e.g., malignancy). In this study we have identified the secretion of soluble ICAM‐1 in tissue culture supernatants from bladder tumour monolayers and in the urine of patients receiving intravesical BCG immunotherapy for superficial bladder cancer. In vitro , small amounts of sICAM‐1 were detected in the tissue culture supernatants of bladder cancer cells, known to constitutively express ICAM‐1. Following stimulation with interferon γ, the levels of sICAM‐1 increased inversely to the levels of cell surface ICAM‐1, suggesting shedding. Induction and augmentation of cell surface ICAM‐1 required de novo mRNA and protein synthesis. However, treatment with cycloheximide, after stimulation with IFN‐γ, resulted in increased levels of membrane associated ICAM‐1. Correspondingly, the level of sICAM‐1 in the supernatant was low in comparison with controls, suggesting that cycloheximide acted via stabilization of membrane ICAM‐1 or via prevention of some enzymatic cleavage event. In vivo , sICAM‐1 can be detected at high levels in patients' urine following immunotherapy of bladder cancer with intravesically administered BCG organisms. Production of sICAM‐1 is transient and occurs only in the first 12 hr following instillation. Furthermore, production of sICAM‐1 is heterogeneous as some patients fail to produce any at all. If the source of sICAM‐1 is the bladder tumour per se, then its detection in urine could indicate a response of the tumour to immunotherapy and indeed may prove a useful indicator of clinical response.