The Role of ICOS/OPN/ICOSL System in Wound Healing, Sepsis and Cancer

ICOS (also known as CD278) is a T cell co-stimulatory molecule, a member of the CD28 family. It wasoriginally identified on activated T cells, but it has been recently detected also in dendritic cells andmacrophages.ICOS binds ICOSL (or B7h), a member of the B7 family. ICOSL is expressed by multiple cell types, such asantigen presenting cells (APC), endothelial cells, epithelial cells, fibroblasts and several types of neoplasticcells. The interaction of ICOSL and ICOS can induce the transmission of “reverse signals” in the cell thatexpresses ICOSL. Moreover, recent data showed that also OPN (Osteopontin) binds ICOSL using a differentbinding site than that used by ICOS and elicits different, often opposite, effects in the immune response,tumor development, and bone metabolism. In particular, ICOSL triggering using a recombinant soluble formof ICOS (ICOS-Fc) inhibits tumor cell migration, tumor angiogenesis, and tumor growth, which are increasedby OPN. Moreover, ICOS-Fc inhibits bone resorption mediated by osteoclasts, whereas OPN is involved inbone deposition.Aim of this thesis was to assess the role of the ICOS/ICOSL interaction in tumor development, working onmultiple myeloma and melanoma; and the relative role in the inflammatory and repair phases ofinflammation, working in skin wound healing and sepsis.1) Multiple myeloma was chosen because it is a bone tumor in which the ICOS/ICOSL interaction mayinfluence both the tumor growth and the osteolytic lesions. Results show that that multiple myeloma cellsexpress high levels of ICOSL and low levels of ICOS, and patients with multiple myeloma display increasedserum levels of soluble forms of both molecules correlating with known parameters of tumor burden.Moreover, treatment of mice with ICOS-Fc loaded in biocompatible biodegradable PLGA nanoparticlesinhibits the growth of myeloma cells in vivo, exerting a predominant anti-angiogenic effect.2) Melanoma was chosen because previous data showed that treatment of mice with ICOS-Fc loaded onPLGA or cyclodextrin nanoparticles strongly inhibits tumor growth and metastatization, and exerts anti-angiogenic effects. Using the B16 mouse melanoma model, we investigated the possibility of using ICOS-Fcin a combination therapy where ICOS-Fc was loaded in Intralipid® nanoemulsions together with thetargeted drug sorafenib, and the chemotherapeutic drug temozolomide. Results show that the combinationtherapy strongly inhibits the tumor growth and angiogenesis, and a key role is played by ICOS-Fc.3) Skin wound healing was chosen because it is a physiologic process in which the inflammatory and therepair phases of inflammation can be easily monitored in mice. Results show that local treatment withICOS-Fc improves wound healing, promotes angiogenesis, preceded by upregulation of IL-6 and VEGFexpression; increases the number of fibroblasts and T cells, whereas it reduces that of neutrophils; andincreases the number of M2 vs. M1 macrophages.4) Sepsis was chosen because it is a pathologic process due to excessive and uncoordinated development ofthe inflammatory and the repair phase of inflammation. Results show that, in sepsis induced by cecalligation and puncture (CLP) in mice, treatment with ICOS-Fc reduces the clinical severity score, plasmacytokines, liver injury, and kidney dysfunction.These data suggest that ICOS-mediated triggering of ICOSL may play a key role in the repair phase ofinflammation, and short circuits of this interaction may be involved in tumor development.