DNA-Demethylating Agents enhance cytolytic activity of CD8+ T Cells and anti-tumor immunity Helen Loo Yau1,2,*, Ankur Chakravarthy1,*, Felipe Campos de Almeida3,4, David Allard5,6, Rajat Singhania1, Ilias Ettayebi1,2, Shu Yi Shen1, Tiago Medina1, Parinaz Mehdipour1, Beatriz Morancho7, Sandra Pommey5, Christian Klein8, Gustavo Amarante-Mendes3,4, David Roulois11, Marcus Butler1, Joaquín Arribas7,9,10,John Stagg5,6,Daniel D. De Carvalho1,2 1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; 2Department of Medical Biophysics, University of Toronto, Toronto, Canada; 3Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil; 4Instituto de Investigação em Imunologia, Institutos Nacionais de Ciência e Tecnologia (INCT-iii), Brazil; 5Centre de recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal, Montréal, QC, Canada; 6Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada 7Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO) and CIBER-ONC, Barcelona, Spain; 8Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Wagistrasse 18, 8952, Schlieren, Switzerland; 9Department of Biochemistry and Molecular Biology Universitat Autònoma de Barcelona, Bellaterra, Spain; 10Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; 11UMR U1236, INSERM, Université de Rennes 1, EFS, Rennes, France * Equal Contributions
Recent studies have shown that DNA methyltransferase inhibitors (DNMTi) can induce IRF7 activation and Type I/III interferon signaling through dsRNA-mediated viral mimicry in cancer cells. By performing a large pan-cancer analysis using TCGA data, we determined that IRF7 activation is associated with higher CD8+ T cell tumor infiltration and higher cytolytic activity across multiple cancer types. Accordingly, we demonstrate that DNMTi treatment results in increased CD8+ T cell tumor infiltration, enhanced cytolytic activity and CD8+ T cell dependent tumor growth inhibition. Finally, we show that DNMTi triggers a process marked by the induction of viral mimicry directly on CD8+ T cells, leading to activation of dsRNA sensing pathway, and up-regulation of T cell activation markers, effector cytokines, and Granzyme B. Taken together, our findings suggest that dsRNA sensing pathway activation in the immune compartment, through pharmacological DNA demethylation, is a viable strategy for boosting anti-tumor immune response.
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