Inducible T-Cell Costimulator Ligand Plays a Dual Role in Melanoma Metastasis upon Binding to Osteopontin or Inducible T-Cell Costimulator.

Davide Raineri,Umberto Dianzani,Beatrice Vilardo,Annalisa Chiocchetti,Giuseppe Cappellano,Elena Canciani,Casimiro Luca Gigliotti,Elena Boggio,Renzo Boldorini,Federica Maione,Chiara Monge,Nausicaa Clemente,Chiara Dianzani

doi:10.3390/biomedicines10010051

Davide Raineri, Umberto Dianzani + Show 11 more

Open Access

https://doi.org/10.3390/biomedicines10010051

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Abstract

Recently, we demonstrated that inducible T-cell costimulator (ICOS) shares its unique ligand (ICOSL) with osteopontin (OPN), and OPN/ICOSL binding promotes tumor metastasis and angiogenesis in the 4T1 breast cancer model. Literature showed that OPN promotes melanoma metastasis by suppressing T-cell activation and recruiting myeloid suppressor cells (MDSC). On the opposite, ICOS/ICOSL interaction usually sustains an antitumor response. Here, we engineered murine B16F10 melanoma cells, by transfecting or silencing ICOSL. In vitro data showed that loss of ICOSL favors anchorage-independent growth and induces more metastases in vivo, compared to ICOSL expressing cells. To dissect individual roles of the three molecules, we compared data from C57BL/6 with those from OPN-KO, ICOS-KO, and ICOSL-KO mice, missing one partner at a time. We found that OPN produced by the tumor microenvironment (TME) favors the metastasis by interacting with stromal ICOSL. This activity is dominantly inhibited by ICOS expressed on TME by promoting Treg expansion. Importantly, we also show that OPN and ICOSL highly interact in human melanoma metastases compared to primary tumors. Interfering with this binding may be explored in immunotherapy either for nonresponding or patients resistant to conventional therapies.

Highlights

This study investigates the role in tumor cell metastasis of the inducible T-cell costimulator (ICOS)/inducible T-cell costimulator ligand (ICOSL)/OPN
The study used wild-type mice and three strains of KO mice, lacking either ICOS, or OPN, or ICOSL. It emerged that the three members of the ICOS/ICOSL/OPN network play distinct and differing roles, possibly acting both at the tumor cell level and at that of the tumor microenvironment (TME)
ICOS and OPN bind to ICOSL, but exert different, often opposing, effects on the cell that expresses ICOSL; (2) OPN binds other surface receptors, such as integrins and CD44; (3) OPN and its ligands (ICOSL, integrins, and CD44) can be expressed by tumor cells and by several cell types of the TME, influencing tumor cell survival, proliferation, and metastasis; (4) ICOS can be expressed by different types of T cells, including effector and

Summary

Introduction

Melanoma is a malignant tumor arising from melanocytes that accounts for only about. 1% of skin cancers [1] but it causes the large majority of skin cancer deaths [2]. Diagnosis is often made at late stages when melanoma cells have already metastasized. Melanoma is a highly immunogenic tumor, and infiltration with cytotoxic CD8+ T cells has been associated with a good prognosis, since they can efficiently kill tumor cells [3]. Melanoma immune escape is primarily due to alterations in antigen expression or presentation, but a role has been ascribed to immunosuppression, mediated in particular regulatory T cells (Tregs) [4,5] and myeloid-derived suppressor cells (MDSCs) [6,7].

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