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.
Yau, Helen Loo and Chakravarthy, Ankur and Campos de Almeida, Felipe and Allard, David and Singhania, Rajat and Ettayebi, Ilias and Shen, Shu Yi and Medina, Tiago and Mehdipour, Parinaz and Morancho, Beatriz and Pommey, Sandra and Klein, Christian and Amarante-Mendes, Gustavo and Roulois, David and Butler, Marcus and Arribas, Joaquín and Stagg, John and De Carvalho, Daniel D., DNA-Demethylating Agents Enhance Cytolytic Activity of CD8 T Cells and Anti-Tumor Immunity (2018). Available at SSRN: https://ssrn.com/abstract=3155506 or http://dx.doi.org/10.2139/ssrn.3155506
This version of the paper has not been formally peer reviewed.
Subscribe to this free journal for more curated articles on this topic
FOLLOWERS
20
PAPERS
9,156
Feedback
Feedback to SSRN
If you need immediate assistance, call 877-SSRNHelp (877 777 6435) in the United States, or +1 212 448 2500 outside of the United States, 8:30AM to 6:00PM U.S. Eastern, Monday - Friday.