Epigenetic modifications upregulate PD-1, CTLA-4, TIM-3 and LAG-3 immune checkpoint genes in breast tumor microenvironment Varun Sasidharan Nair1, Haytham El Salhat2,3, Anne John4, Bassam R. Ali4, Eyad Elkord1,5,* 1Cancer Research Center, Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar; 2 Oncology Department, Al Noor Hospital, Abu Dhabi, United Arab Emirates; 3 Oncology Department, Tawam Hospital, Al Ain, United Arab Emirates; 4College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 5Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom *Corresponding author: email@example.com or firstname.lastname@example.org High expression of immune checkpoints in tumor microenvironment play a significant role in inhibiting anti-tumor immunity, and it is associated with poor prognosis and cancer progression. The major epigenetic modifications in both histone and DNA could be involved in the upregulation of these immune checkpoints in cancer. Herein, we first assessed the expression level of different immune checkpoint genes in breast tissues, and found that PD-1, CTLA-4, TIM-3 and LAG-3 are significantly upregulated in breast tumor tissues, compared with breast normal tissues. To excavate the epigenetic modifications behind this upregulation, we checked both DNA and histone methylations of these immune checkpoints. Interestingly, we found that the CpG islands in the promoter region of PD-1, CTLA-4 and TIM-3 were significantly hypomethylated in tumor tissues compared with normal tissues, but not LAG-3. The demethylation percentage of immune checkpoint genes was highest in CTLA-4 followed by PD-1 then TIM-3 and finally LAG-3. Moreover, bindings of trimethyl histone H3 lysine 9 (H3K9me3) and histone H3 lysine 27 (H3K27me3) were reduced in the promoter loci of PD-1, CTLA-4, TIM-3 and LAG3 in tumor tissues. These results show that both DNA and histone epigenetic modifications are involved in the upregulation of PD-1, CTLA-4 and TIM-3 in breast tumor tissue. Additionally, only histone methylation is engaged with the upregulation of LAG-3 in breast tumor microenvironment. Taken together, our data reveal one of the underlying mechanisms involved in the upregulation of multiple immune checkpoints in breast tumor microenvironment, and these epigenetic modifications could be useful diagnostic and/or prognostic biomarkers in breast cancer.
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