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DNA-Demethylating Agents Enhance Cytolytic Activity of CD8 T Cells and Anti-Tumor Immunity

52 Pages Posted: 4 Apr 2018 Publication Status: Review Complete

See all articles by Helen Loo Yau

Helen Loo Yau

University of Toronto - Princess Margaret Cancer Centre

Ankur Chakravarthy

University of Toronto - Princess Margaret Cancer Centre

Felipe Campos de Almeida

University of São Paulo (USP) - Instituto de Ciências Biomédicas

David Allard

University of Montreal - Faculté de Pharmacie

Rajat Singhania

University of Toronto - Princess Margaret Cancer Centre

Ilias Ettayebi

University of Toronto - Princess Margaret Cancer Centre

Shu Yi Shen

University of Toronto - Princess Margaret Cancer Centre

Tiago Medina

University of Toronto - Princess Margaret Cancer Centre

Parinaz Mehdipour

University of Toronto - Princess Margaret Cancer Centre

Beatriz Morancho

Vall d’Hebron Institute of Oncology (VHIO) - Preclinical Research Program

Sandra Pommey

University of Montreal - Institut du Cancer de Montréal

Christian Klein

Roche - Roche Innovation Center Zurich

Gustavo Amarante-­Mendes

University of São Paulo (USP) - Instituto de Ciências Biomédicas

David Roulois

Université de Rennes 1 - INSERM

Marcus Butler

University of Toronto - Princess Margaret Cancer Centre

Joaquín Arribas

Vall d’Hebron Institute of Oncology (VHIO) - Preclinical Research Program

John Stagg

University of Montreal - Faculté de Pharmacie

Daniel D. De Carvalho

University of Toronto - Princess Margaret Cancer Centre

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Abstract

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.

Suggested Citation

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.

Helen Loo Yau

University of Toronto - Princess Margaret Cancer Centre

5th Floor Rm 5-206
610 University Ave
Toronto, ON M5G 2M9 M5G 2M9
Canada

Ankur Chakravarthy

University of Toronto - Princess Margaret Cancer Centre

5th Floor Rm 5-206
610 University Ave
Toronto, ON M5G 2M9 M5G 2M9
Canada

Felipe Campos de Almeida

University of São Paulo (USP) - Instituto de Ciências Biomédicas

São Paulo
Brazil

David Allard

University of Montreal - Faculté de Pharmacie

Pavillon Jean-Coutu
2940, chemin de Polytechnique, H3T 1J4
Quebec
Canada

Rajat Singhania

University of Toronto - Princess Margaret Cancer Centre

5th Floor Rm 5-206
610 University Ave
Toronto, ON M5G 2M9 M5G 2M9
Canada

Ilias Ettayebi

University of Toronto - Princess Margaret Cancer Centre

5th Floor Rm 5-206
610 University Ave
Toronto, ON M5G 2M9 M5G 2M9
Canada

Shu Yi Shen

University of Toronto - Princess Margaret Cancer Centre

5th Floor Rm 5-206
610 University Ave
Toronto, ON M5G 2M9 M5G 2M9
Canada

Tiago Medina

University of Toronto - Princess Margaret Cancer Centre

5th Floor Rm 5-206
610 University Ave
Toronto, ON M5G 2M9 M5G 2M9
Canada

Parinaz Mehdipour

University of Toronto - Princess Margaret Cancer Centre

5th Floor Rm 5-206
610 University Ave
Toronto, ON M5G 2M9 M5G 2M9
Canada

Beatriz Morancho

Vall d’Hebron Institute of Oncology (VHIO) - Preclinical Research Program

CELLEX CENTER
Calle Natzaret, 115-117
Barcelona, 08035
Spain

Sandra Pommey

University of Montreal - Institut du Cancer de Montréal

Quebec
Canada

Christian Klein

Roche - Roche Innovation Center Zurich

Wagistrasse 18, 8952
Schlieren
Switzerland

Gustavo Amarante-­Mendes

University of São Paulo (USP) - Instituto de Ciências Biomédicas

São Paulo
Brazil

David Roulois

Université de Rennes 1 - INSERM

Rennes
France

Marcus Butler

University of Toronto - Princess Margaret Cancer Centre

5th Floor Rm 5-206
610 University Ave
Toronto, ON M5G 2M9 M5G 2M9
Canada

Joaquín Arribas

Vall d’Hebron Institute of Oncology (VHIO) - Preclinical Research Program

CELLEX CENTER
Calle Natzaret, 115-117
Barcelona, 08035
Spain

John Stagg

University of Montreal - Faculté de Pharmacie

Pavillon Jean-Coutu
2940, chemin de Polytechnique, H3T 1J4
Quebec
Canada

Daniel D. De Carvalho (Contact Author)

University of Toronto - Princess Margaret Cancer Centre ( email )

5th Floor Rm 5-206
610 University Ave
Toronto, ON M5G 2M9 M5G 2M9
Canada

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