GM-CSF Nitration Is a New Driver of Myeloid Suppressor Cell Activity in Tumors
Bianca Calì1, Andrielly H R Agnellini1,2, Chiara Cioccarelli1,3
1Department of Biomedical Science, University of Padua, Padua, Italy.
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.
Insights
Reactive nitrogen species (RNS) modify granulocyte-macrophage colony-stimulating factor (GM-CSF), promoting immunosuppressive myeloid cells in tumors. Targeting nitrated GM-CSF could enhance anti-cancer immunity.
Area of Science:
- Immunology
- Cancer Biology
- Biochemistry
Background:
- Reactive oxygen and nitrogen species (RNS) modulate immune cell functions in the tumor microenvironment (TME).
- Tumor-infiltrating myeloid cells (TIMs) promote cancer progression by suppressing anti-tumor immunity via oxidative/nitrosative stress.
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates TIM expansion and differentiation in tumors.
Purpose of the Study:
- To investigate the impact of RNS on GM-CSF activity within the TME.
- To determine if GM-CSF post-translational modifications influence immunosuppressive myeloid cell expansion.
- To identify potential therapeutic targets for remodeling the TME and enhancing anti-cancer immunity.
Main Methods:
- Analysis of GM-CSF post-translational modifications triggered by RNS.
- Assessment of myeloid cell subsets expansion in tumor-bearing hosts.
- Quantification of nitrated tryptophan in GM-CSF from colorectal cancer patient tumors versus non-neoplastic tissues.
Main Results:
- RNS significantly alter GM-CSF activity through post-translational modifications.
- Nitration of a specific tryptophan residue in GM-CSF promotes the expansion of highly immunosuppressive myeloid cells.
- Elevated levels of nitrated tryptophan in GM-CSF were observed in colorectal cancer tumors compared to normal tissues.
Conclusions:
- GM-CSF activity is critically regulated by RNS-induced nitration.
- Targeting nitrated GM-CSF offers a novel strategy to reduce immunosuppression in the TME.
- Modulating GM-CSF nitration may be a promising approach to enhance anti-cancer immune responses.
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