Osteopontin binds ICOSL promoting tumor metastasis
Davide Raineri, Chiara Dianzani, Giuseppe Cappellano, Federica Maione, Gianluca Baldanzi, Ilaria Iacobucci, Nausicaa Clemente, Giulia Baldone, Elena Boggio, Casimiro Luca Gigliotti, Renzo Boldorini, José María Rojo, Maria Monti, Leila Birolo, Umberto Dianzani, Annalisa Chiocchetti
Abstract
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.