Increased CD4(+) T cell lineage commitment determined by CpG methylation correlates with better prognosis in urinary bladder cancer patients. Ahlén Bergman, E., Hartana, C. A., Johansson, M., Linton, L. B, Berglund, S., Hyllienmark, M., Lundgren, C., Holmström, B., Palmqvist, K., Hansson, J., Alamdari, F., Huge, Y., Aljabery, F., Riklund, K., Winerdal, M. E, Krantz, D., Zirakzadeh, A A., Marits, P., Sjöholm, L. K, Sherif, A., & Winqvist, O. Clinical epigenetics, 10(1):102–102, August, 2018.
Increased CD4(+) T cell lineage commitment determined by CpG methylation correlates with better prognosis in urinary bladder cancer patients [link]Paper  doi  abstract   bibtex   
BACKGROUND: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4(+) T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4(+) T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy. RESULTS: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4(+) lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4(+) lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p \textless 0.0001, IL13 -11 bp p \textless 0.05, IL17A -122 bp p \textless 0.01 and FOXP3 -77 bp p \textgreater 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4(+) T cells for all four investigated loci, most prominently in IFNG p \textless 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4(+) T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3. CONCLUSION: Increased lineage commitment in CD4(+) T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4(+) T cell lineages as a useful readout for clinical staging.
@article{ahlen_bergman_increased_2018,
	title = {Increased {CD}4(+) {T} cell lineage commitment determined by {CpG} methylation correlates with better prognosis in urinary bladder cancer patients},
	volume = {10},
	issn = {1868-7083},
	url = {https://www.ncbi.nlm.nih.gov/pubmed/30075815},
	doi = {10.1186/s13148-018-0536-6},
	abstract = {BACKGROUND: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4(+) T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4(+) T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy. RESULTS: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4(+) lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4(+) lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p {\textless} 0.0001, IL13 -11 bp p {\textless} 0.05, IL17A -122 bp p {\textless} 0.01 and FOXP3 -77 bp p {\textgreater} 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4(+) T cells for all four investigated loci, most prominently in IFNG p {\textless} 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4(+) T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3. CONCLUSION: Increased lineage commitment in CD4(+) T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4(+) T cell lineages as a useful readout for clinical staging.},
	language = {eng},
	number = {1},
	journal = {Clinical epigenetics},
	author = {Ahlén Bergman, Emma and Hartana, Ciputra Adijaya and Johansson, Markus and Linton, Ludvig B and Berglund, Sofia and Hyllienmark, Martin and Lundgren, Christian and Holmström, Benny and Palmqvist, Karin and Hansson, Johan and Alamdari, Farhood and Huge, Ylva and Aljabery, Firas and Riklund, Katrine and Winerdal, Malin E and Krantz, David and Zirakzadeh, A Ali and Marits, Per and Sjöholm, Louise K and Sherif, Amir and Winqvist, Ola},
	month = aug,
	year = {2018},
	keywords = {*CD4-positive T lymphocytes, *DNA Methylation, *DNA methylation, *Urinary bladder neoplasms, Aged, Aged, 80 and over, CD4-Positive T-Lymphocytes/*cytology/immunology, Cell Differentiation, Cell Lineage, Cells, Cultured, CpG Islands, Cystectomy, Drug Therapy, Epigenesis, Genetic, Female, Forkhead Transcription Factors/genetics, Humans, Interferon-gamma/genetics, Interleukin-13/genetics, Interleukin-17/genetics, Male, Middle Aged, Neoadjuvant Therapy, Neoplasm Staging, Prognosis, Sequence Analysis, DNA/*methods, Treatment Outcome, Urinary Bladder Neoplasms/genetics/immunology/*pathology/*surgery},
	pages = {102--102}
}
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