Document Type
Journal Article
Publication Title
Frontiers in Immunology
Volume
14
PubMed ID
37197667
Publisher
Frontiers
School
School of Medical and Health Sciences
RAS ID
60230
Funders
National Health and Medical Research Council / Veterans Affairs Merit Review Award 5I01BX001228 (to MF) / NIH/NCI R01CA197919 (to MF), 1R03CA125833 (to MF), NIH/NIAID R01 AI156534 (to MF), Cancer League of Colorado (to MF) / Cancer and Palliative Care Research and Evaluation Unit WAPCN Small Grants 2010/11 (to MZ) / University of Colorado Cancer Center (UCCC) Support Grant (P30CA046934) / Skin Diseases Research Cores Grant (P30AR057212)
Grant Number
NHMRC Number : 101334
Abstract
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an immune checkpoint expressed in regulatory T (Treg) cells and activated T lymphocytes. Despite its potential as a treatment strategy for melanoma, CTLA-4 inhibition has limited efficacy. Using data from The Cancer Genome Atlas (TCGA) melanoma database and another dataset, we found that decreased CTLA4 mRNA was associated with a poorer prognosis in metastatic melanoma. To investigate further, we measured blood CTLA4 mRNA in 273 whole-blood samples from an Australian cohort and found that it was lower in metastatic melanoma than in healthy controls and associated with worse patient survival. We confirmed these findings using Cox proportional hazards model analysis and another cohort from the US. Fractionated blood analysis revealed that Treg cells were responsible for the downregulated CTLA4 in metastatic melanoma patients, which was confirmed by further analysis of published data showing downregulated CTLA-4 surface protein expression in Treg cells of metastatic melanoma compared to healthy donors. Mechanistically, we found that secretomes from human metastatic melanoma cells downregulate CTLA4 mRNA at the post-transcriptional level through miR-155 while upregulating FOXP3 expression in human Treg cells. Functionally, we demonstrated that CTLA4 expression inhibits the proliferation and suppressive function of human Treg cells. Finally, miR-155 was found to be upregulated in Treg cells from metastatic melanoma patients compared to healthy donors. Our study provides new insights into the underlying mechanisms of reduced CTLA4 expression observed in melanoma patients, demonstrating that post-transcriptional silencing of CTLA4 by miRNA-155 in Treg cells may play a critical role. Since CTLA-4 expression is downregulated in non-responder melanoma patients to anti-PD-1 immunotherapy, targeting miRNA-155 or other factors involved in regulating CTLA4 expression in Treg cells without affecting T cells could be a potential strategy to improve the efficacy of immunotherapy in melanoma. Further research is needed to understand the molecular mechanisms regulating CTLA4 expression in Treg cells and identify potential therapeutic targets for enhancing immune-based therapies.
DOI
10.3389/fimmu.2023.1173035
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Vaddi, P. K., Osborne, D. G., Nicklawsky, A., Williams, N. K., Menon, D. R., Smith, D., ... & Fujita, M. (2023). CTLA4 mRNA is downregulated by miR-155 in regulatory T cells, and reduced blood CTLA4 levels are associated with poor prognosis in metastatic melanoma patients. Frontiers in Immunology, 14, Article 1173035. https://doi.org/10.3389/fimmu.2023.1173035