Epigenetic regulation of immune checkpoints and T cell exhaustion markers in tumor-infiltrating T cells of colorectal cancer patients

Nair, VS; Saleh, R; Toor, SM; Taha, RZ; Ahmed, AA; Kurer, MA; Murshed, K; Nada, MA; Elkord, E

Abstract

Aim: To elucidate the epigenetic alterations behind the upregulation of immune checkpoints and T cell exhaustion markers in colorectal cancer (CRC) patients. Materials & methods: mRNA expressions of different immune checkpoint/exhaustion markers were analyzed by quantitative real-time reverse transcriptase PCR and epigenetic investigations were performed using bisulfite sequencing and chromatin immunoprecipitation quantitative PCR. Results: mRNA expressions of PD-1, TIM-3, CTLA-4, PD-L1 and TOX2 were significantly upregulated in CD4+ and CD8+ tumor-infiltrating lymphocytes and bulk CRC tumor tissues. Histone 3 lysine 9 trimethylation was downregulated and histone 3 lysine 4 trimethylation was upregulated in PD-L1 and TOX2 promoters in tumor tissues, suggesting that PD-L1 and TOX2 upregulation in CRC tumors could be mediated by activating histone 3 lysine 4 trimethylation. Conclusion: Epigenetic modifications in promoters of immune checkpoint and T cell exhaustion genes could induce their upregulation, and potentially implicate the use of epigenetic modifiers to enhance antitumor immunity in CRC patients.

• Journal Article Type: Article
• Acceptance Date: Sep 17, 2020
• Online Publication Date: Nov 10, 2020
• Publication Date: Nov 10, 2020
• Deposit Date: Dec 18, 2020
• Journal: Epigenomics
• Print ISSN: 1750-1911
• Electronic ISSN: 1750-192X
• Publisher: Future Medicine
• Volume: 12
• Issue: 21
• Pages: 1871-1882
• DOI: https://doi.org/10.2217/epi-2020-0267
• Publisher URL: https://doi.org/10.2217/epi-2020-0267
• Related Public URLs: http://www.futuremedicine.com/loi/epi
• Additional Information: Funders : Qatar Foundation; Projects : VR04