15 p.-8 fig.-2 tab.
ICOSL/ICOS are costimulatory molecules pertaining to immune checkpoints; their binding transduces signals having anti-tumor activity. Osteopontin (OPN) is here identified as a ligand for ICOSL. OPN binds a different domain from that used by ICOS, and the binding induces a conformational change in OPN, exposing domains that are relevant for its functions.Here we show that in vitro, ICOSL triggering by OPN induces cell migration, while inhibiting anchorage-independent cell growth. The mouse 4T1 breast cancer model confirms these data. In vivo, OPN-triggering of ICOSL increases angiogenesis and tumor metastatization. The findings shed new light on ICOSL function and indicate that another partner beside ICOS may be involved; they also provide a rationale for developing alternative therapeutic approaches targeting this molecular trio.
This work was supported by the Italian Ministry of Education, University and Research (MIUR) program “Departments of Excellence 2018–2022”, FOHN and AGING Projects, Fondazione Cariplo 2019–3277 to A.C., the Associazione Italiana Ricerca sul Cancro (IG 20714, AIRC, Milano), Fondazione Amici di Jean (Torino), and Fondazione Cariplo (2017–0535) to U.D., National Ministry of University and research PRIN 2017 (grant 201799WCRH) to G.B., Consorzio Interuniversitario di Biotecnologie (CIB) bando “Network-CIB: Catalisi dell’Innovazione nelle biotecnologie” to G.B.