Loo Yau et al. examined the effects of DAC (decitabine, a DNA hypomethylation agent) on murine and human CD8+ T cells. In a mouse tumor model, in vivo DAC treatment resulted in a CD8+ T cell-dependent reduction in tumor growth and enhanced production of cytotoxic effector proteins by TILs. Ex vivo activation of CD8+ T cells from healthy human donors in the presence of DAC resulted in reduced proliferation, but enrichment of cells with enhanced cytotoxic capacity (also observed in CD8+ T cells from cancer patients), differential regulation of canonical T cell transcription factors, and amplification of NFAT-related transcriptional signaling.
Contributed by Margot O’Toole
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.
Author Info: (1) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. (
Author Info: (1) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. (2) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (3) 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. (4) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. (5) 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. (6) Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO) and CIBERONC, 08035 Barcelona, Spain. (7) 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. (8) Centre de recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montréal, QC H2X 0A9, Canada. (9) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952 Schlieren, Switzerland. (10) UMR U1236, INSERM, Université de Rennes 1, EFS, 35000 Rennes, France. (11) 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. (12) 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.
