GM-CSF Nitration Is a New Driver of Myeloid Suppressor Cell Activity in Tumors.

Bianca Calì,Francesco Zonta,Giorgio Arrigoni,Chiara Cioccarelli,Ilaria Marigo,Antonella Viola,Andrielly H R Agnellini,Claudia Mescoli,Ricardo Sanchez-Rodriguez,Giulia Ilaria Toffolo,Laura Albertoni,Andrea Predonzani,Vincenzo Bronte,Barbara Molon

doi:10.3389/fimmu.2021.718098

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.

Highlights

Host immune system can intercept, recognize and neutralize tumor cell clones
We reasoned that post-translational modification (PTM) could be responsible for the antithetical course of action of granulocyte-macrophage colony-stimulating factor (GM-CSF) in tumors
The accumulation of myeloid immunosuppressive cells (MDSCs) at the tumor site correlates with bad prognosis in different type of cancers [22] and it has been well-established that GM-CSF acts as driver for myeloid derived suppressor cells (MDSCs) differentiation in tumors [12]

Summary

Introduction

Host immune system can intercept, recognize and neutralize tumor cell clones. Following this paradigm, cancer immunotherapy has become a tangible opportunity for the treatment of different cancers as the metastatic melanoma, lung cancer and colorectal cancer [1, 2]. One of the key suppressive mechanisms tailoring cancer progression is the appearance of an unbalanced myelopoiesis in tumor-bearing hosts [3] This process leads to the expansion and differentiation of distinctive myeloid cell subsets that are principally involved in promoting T cell unresponsiveness toward tumor antigens [4, 5]. Other experimental evidence paradoxically indicates that GM-CSF acts as a potent immunostimulatory product and its efficacy as vaccine-adjuvant has been demonstrated in different regimens [13, 14] Reasonable explanations for this antithetical conduct could be found in a quantitative difference in location and dosage of the very same cytokine in tumors [15] or most likely, in a qualitative divergent tumor-related mechanism. GM-CSF can act in cancer as corrupted cytokine, co-opted by the tumor itself to sculpt an immunosuppressive environment establishing its immune privilege [16]

Methods

Results

Conclusion