GM-CSF Nitration Is a New Driver of Myeloid Suppressor Cell Activity in Tumors
Bianca Calì, Andrielly H.R. Agnellini, Chiara Cioccarelli, Ricardo Sánchez‐Rodríguez, Andrea Predonzani, Giulia Ilaria Toffolo, Antonella Viola, Vincenzo Bronte, Giorgio Arrigoni, Francesco Zonta, Laura Albertoni, Claudia Mescoli, Ilaria Marigo, Barbara Molon
Abstract
Reactive oxygen species, including RNS, contribute to the control of multiple immune cell functions within the tumor microenvironment (TME). Tumor-infiltrating myeloid cells (TIMs) represent the archetype of tolerogenic cells that actively contribute to dismantle effective immunity against cancer. TIMs inhibit T cell functions and promote tumor progression by several mechanisms including the amplification of the oxidative/nitrosative stress within the TME. In tumors, TIM expansion and differentiation is regulated by the granulocyte-macrophage colony-stimulating factor (GM-CSF), which is produced by cancer and immune cells. Nevertheless, the role of GM-CSF in tumors has not yet been fully elucidated. In this study, we show that GM-CSF activity is significantly affected by RNS-triggered post-translational modifications. The nitration of a single tryptophan residue in the sequence of GM-CSF nourishes the expansion of highly immunosuppressive myeloid subsets in tumor-bearing hosts. Importantly, tumors from colorectal cancer patients express higher levels of nitrated tryptophan compared to non-neoplastic tissues. Collectively, our data identify a novel and selective target that can be exploited to remodel the TME and foster protective immunity against cancer.