Dissecting the ICOS/ICOSL/OPN triangle in tumors in order to develop combination therapies targeting immune checkpoints

Background ICOS is a T cell costimulatory molecule and its triggering by ICOSL regulates T cell function in lymphoid organs and inflamed sites. It binds ICOSL expressed in many cell types. OPN is both an extracellular matrix protein and a soluble cytokine involved in inflammation, cell migration and tumor development. It binds to several receptors, including integrins and CD44, using distinct binding sites. We recently found that OPN binds also ICOSL, without interfering with the binding site used by ICOS. ICOSL triggering by ICOS or OPN induces different, often opposite, effects, since OPN induces tumor cell migration, metastatization and angiogenesis, whereas ICOS inhibits these functions in a dominant negative manner. In Western countries, diffusion of effective therapies for hepatic viral infections is changing the aetiology of hepatocellular carcinoma (HCC) with an increasing importance of non-alcoholic steatohepatitis (NASH) which is expected to become the prevalent cause of HCC in the next decade. Compared to HCC with other etiologies, NASH-HCC responds poorly to therapy with anti-PD1/ PDL1 inhibitors and the 5-year survival rate is quite low. Hypothesis We recently found that hepatic ICOS+CD8+ T cells and ICOSL+ M2-like macrophages are involved in liver repair after acute inflammatory injury, whereas hepatic PD1+ICOS+CD8+ T cells and ICOSL+ M2-like macrophages are involved in the chronic liver damage in NASH. Intriguingly, other authors showed that PD1+CD8+ T cells are involved in development of NASH-HCC. We suggest that the ICOS/ICOSL interaction is normally involved in liver repair but, in NAFLD, it may build up a short circuit involved in development of NASH and NASH-HCC.