1. DNA hypomethylating agents increase activation and cytolytic activity of CD8 + T cells.
- Author
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Loo Yau H, Bell E, Ettayebi I, de Almeida FC, Boukhaled GM, Shen SY, Allard D, Morancho B, Marhon SA, Ishak CA, Gonzaga IM, da Silva Medina T, Singhania R, Chakravarthy A, Chen R, Mehdipour P, Pommey S, Klein C, Amarante-Mendes GP, Roulois D, Arribas J, Stagg J, Brooks DG, and De Carvalho DD
- Subjects
- DNA Methylation immunology, Humans, NFATC Transcription Factors immunology, Perforin immunology, CD8-Positive T-Lymphocytes immunology, CpG Islands immunology, DNA Methylation drug effects, Decitabine pharmacology, Granzymes immunology, Lymphocyte Activation drug effects
- Abstract
We demonstrate that DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8
+ T cells. In vivo HMA treatment promotes CD8+ T cell tumor infiltration and suppresses tumor growth via CD8+ T cell-dependent activity. Ex vivo, HMAs enhance primary human CD8+ T cell activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T cell activation-related transcriptional networks, culminating with over-activation of NFATc1 short isoforms. Mechanistically, demethylation of an intragenic CpG island immediately downstream to the 3' UTR of the short isoform was associated with antisense transcription and alternative polyadenylation of NFATc1 short isoforms. High-dimensional single-cell mass cytometry analyses reveal a selective effect of HMAs on a subset of human CD8+ T cell subpopulations, increasing both the number and abundance of a granzyme Bhigh , perforinhigh effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response., Competing Interests: Declaration of interests D.D.D.C. received research funds from Pfizer and Nektar Therapeutics. D.D.D.C. is a co-founder and shareholder of DNAMx, Inc. C.K. is employed by and owns stock, patents, and royalties with Roche. J.S. is a permanent scientific advisory board member for and owns stock in Surface Oncology., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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