DNA hypomethylating agents increase activation and cytolytic activity of CD8 + T cells.

Autor:	Loo Yau H; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada., Bell E; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Ettayebi I; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada., de Almeida FC; Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; Instituto de Investigação em Imunologia, Institutos Nacionais de Ciência e Tecnologia (INCT-iii), São Paulo 05403-900, Brazil., Boukhaled GM; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada., Shen SY; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Allard D; Centre de recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montréal, QC H2X 0A9, Canada; Faculté de Pharmacie, Université de Montréal, Montréal, QC H3T 1J4, Canada., Morancho B; Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO) and CIBERONC, 08035 Barcelona, Spain., Marhon SA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Ishak CA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Gonzaga IM; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., da Silva Medina T; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Translational Immuno-oncology Laboratory, A.C. Camargo Cancer Center, São Paulo 01509-001, Brazil., Singhania R; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Chakravarthy A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Chen R; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada., Mehdipour P; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Pommey S; Centre de recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montréal, QC H2X 0A9, Canada., Klein C; Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952 Schlieren, Switzerland., Amarante-Mendes GP; Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; Instituto de Investigação em Imunologia, Institutos Nacionais de Ciência e Tecnologia (INCT-iii), São Paulo 05403-900, Brazil., Roulois D; UMR U1236, INSERM, Université de Rennes 1, EFS, 35000 Rennes, France., Arribas J; Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO) and CIBERONC, 08035 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain; Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain., Stagg J; Centre de recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montréal, QC H2X 0A9, Canada; Faculté de Pharmacie, Université de Montréal, Montréal, QC H3T 1J4, Canada., Brooks DG; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada., De Carvalho DD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: daniel.decarvalho@uhnresearch.ca.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2021 Apr 01; Vol. 81 (7), pp. 1469-1483.e8. Date of Electronic Publication: 2021 Feb 19.
DOI:	10.1016/j.molcel.2021.01.038
Abstrakt:	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 B high , perforin high 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.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu