Role of Arginase 1 and Nitric Oxide Synthase 2 as enzymatic mediators of the immunosuppressive activity in tumor-infiltrating myeloid derived suppressor cells
Year: 2012
Type: dissertation
Abstract: MDSCs (myeloid derived suppressor cells) are one of the most important immunoregulatory populations involved in the generation of a permissive environment allowing tumor escape, progression and spreading. In physiologic conditions MDSCs protect the organism from exacerbated immune responses in order to protect surrounding tissues from damage. During tumor growth, cancer cells produce TDSFs (tumor derived soluble factors), which induce MDSC accumulation and their acquisition of a persistent suppressive activity. Among the several mechanisms exploited by MDSCs to exert their suppressive function, L-arginine metabolism seems to be fundamental for the alteration of the tumor microenvironment and for the generation of T effector cell dysfunctions. This work highlights the in vivo requirement for ARG1 and NOS2 in the biology of MDSCs during tumor development. MDSCs are known for their phenotypic and functional complexity. It is clear that many factors can shape their identity and function: here we show, indeed that tumor microenvironment can “educate” them progressively. We illustrate that ARG1 and NOS2 are fundamental for MDSC-mediated T cell suppression in vivo but also for the expansion of the suppressive subsets of MDSCs. L-arginine metabolism mediated by these enzymes is crucial for tumor spreading and metastasis, as depletion of either enzyme produces a 50-75% reduction in the number of lung metastases. Finally, we show that the effects mediated by the novel drug AT38 are mediated by ARG1/NOS2 reduction and sufficient to improve ACT (adoptive cell therapy) therapeutic approaches. Data here produced represent a body of evidence that could be exploited for improving the efficiency of anti-cancer therapies, and identifies ARG1 and NOS2 as key targets for restoring T cell mediated tumor responses.
Author: Serena Zilio
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3959955