journal contribution
posted on 2023-12-01, 07:23 authored by Sotiria Pinioti, Himal Sharma, Nina C. Flerin, Qian Yu, Amalia Tzoumpa, Sarah Trusso Cafarello, Elien De Bousser, Nico Callewaert, Guillaume Oldenhove, Susan Schlenner, Bernard Thienpont, Abhishek D. Garg, Mario Di Matteo, Massimiliano Mazzone Additional evidence of FucoLOW Tregs predicting better outcome in cancer patients. Related to figure 7. (A-E) Pearson’s correlation plots for FucoLOW Tregs signature vs. bulk-transcriptome signatures of endothelial cells, fibroblasts, macrophages, melanocytic (cancer) cells or Tregs in TCGA dataset from melanoma cancer patients shown in Fig 7F-H. (F) Gene Set Enrichment score of Golgi-fucosylation signature in Tregs derived from PBMCs, tumor-derived Tregs and Tregs derived from Normal Breast Parenchyma (NBP) in published RNA-seq data derived from breast cancer patients. (G) Graphical abstract of the study: An in vitro metabolic CRISPR/cas9 screen was performed in in vitro-induced Tregs revealing positive and negative regulators of Foxp3 expression. Slc35c1 was revealed as the top positive regulator of Foxp3 and its role in Tregs biology was studied in vitro and in vivo. Slc35c1-deficient Tregs exhibit impaired fucosylation, reduced Foxp3 and PD-1 expression and increased IFNγ production accompanied by reduced suppressive function. In vivo suppressive assay with sgSlc35c1 Tregs transfer in Rag2-/- tumor-bearing mice led to reduced tumor growth, high infiltration of CD4+ and CD8+ T cells and reduced number of tumor-associated macrophages. In colorectal cancer patients, FucoLOW Tregs are highly immunogenic compared to FucoHIGH Tregs. In melanoma cancer patients FucoLOW signature mainly derived by Tregs, is correlated with high overall survival and better response to immunotherapy.
Funding
HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA)
HORIZON EUROPE European Research Council (ERC)
Stichting Tegen Kanker (Fondation Contre le Cancer)
Vlaams Instituut voor Biotechnologie (VIB)
Fonds Wetenschappelijk Onderzoek (FWO)
KU Leuven (Katholieke Universiteit Leuven)
Kom op tegen Kanker (Fight Cancer)
VLIRUOS (VLIR-UOS)
History
ARTICLE ABSTRACT
Forkhead box P3 (Foxp3)–expressing regulatory T cells (Treg) are the guardians of controlled immune reactions and prevent the development of autoimmune diseases. However, in the tumor context, their increased number suppresses antitumor immune responses, indicating the importance of understanding the mechanisms behind their function and stability. Metabolic reprogramming can affect Foxp3 regulation and, therefore, Treg suppressive function and fitness. Here, we performed a metabolic CRISPR/Cas9 screen and pinpointed novel candidate positive and negative metabolic regulators of Foxp3. Among the positive regulators, we revealed that targeting the GDP-fucose transporter Slc35c1, and more broadly fucosylation (Fuco), in Tregs compromises their proliferation and suppressive function both in vitro and in vivo, leading to alteration of the tumor microenvironment and impaired tumor progression and protumoral immune responses. Pharmacologic inhibition of Fuco dampened tumor immunosuppression mostly by targeting Tregs, thus resulting in reduced tumor growth. In order to substantiate these findings in humans, tumoral Tregs from patients with colorectal cancer were clustered on the basis of the expression of Fuco-related genes. FucoLOW Tregs were found to exhibit a more immunogenic profile compared with FucoHIGH Tregs. Furthermore, an enrichment of a FucoLOW signature, mainly derived from Tregs, correlated with better prognosis and response to immune checkpoint blockade in melanoma patients. In conclusion, Slc35c1-dependent Fuco is able to regulate the suppressive function of Tregs, and measuring its expression in Tregs might pave the way towards a useful biomarker model for patients with cancer.See related Spotlight by Silveria and DuPage, p. 1570
