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

Author(s):Show less -

Yau, Helen Loo ^{[1, 2]} ; Bell, Emma ^[2] ; Ettayebi, Ilias ^{[1, 2]} ; de Almeida, Felipe Campos ^{[3, 4]} ; Boukhaled, Giselle M. ^{[5, 2]} ; Shen, Shu Yi ^[2] ; Allard, David ^{[6, 7, 8]} ; Morancho, Beatriz ^{[9, 10]} ; Marhon, Sajid A. ^[2] ; Ishak, Charles A. ^[2] ; Gonzaga, Isabela M. ^[2] ; Medina, Tiago da Silva ^{[2, 11]} ; Singhania, Rajat ^[2] ; Chakravarthy, Ankur ^[2] ; Chen, Raymond ^{[1, 2]} ; Mehdipour, Parinaz ^[2] ; Pommey, Sandra ^{[7, 8]} ; Klein, Christian ^[12] ; Amarante-Mendes, Gustavo P. ^{[3, 4]} ; Roulois, David ^[13] ; Arribas, Joaquin ^{[9, 10, 14, 15]} ; Stagg, John ^{[6, 7, 8]} ; Brooks, David G. ^{[5, 2]} ; De Carvalho, Daniel D. ^{[1, 2]}

Affiliation:Show less -

^[1] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7 - Canada

^[2] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2C1 - Canada

^[3] Univ Sao Paulo, Inst Ciencias Biorned, BR-05508000 Sao Paulo - Brazil

^[4] Inst Nacionais Ciencia & Tecnol INCT Iii, Inst Invest Imunol, BR-05403900 Sao Paulo - Brazil

^[5] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8 - Canada

^[6] Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4 - Canada

^[7] Ctr Rech Ctr Hosp Univ Montreal, Montreal, PQ H2X 0A9 - Canada

^[8] Inst Canc Montreal, Montreal, PQ H2X 0A9 - Canada

^[9] Vall dHebron Inst Oncol VHIO, Preclin Res Program, Barcelona 08035 - Spain

^[10] CIBERONC, Barcelona 08035 - Spain

^[11] AC Camargo Canc Ctr, Translat Immunooncol Lab, BR-01509001 Sao Paulo - Brazil

^[12] Roche Innovat Ctr Zurich, Roche Pharma Res & Early Dev, Wagistr 10, CH-8952 Schlieren - Switzerland

^[13] Univ Rennes 1, EFS, INSERM, UMR U1236, F-35000 Rennes - France

^[14] Inst Catalana Recerca & Estudis Avangats ICREA, Barcelona 08010 - Spain

^[15] IMIM Hosp Mar Med Res Inst, Canc Res Program, Barcelona 08003 - Spain

• Document type: Journal article
• Source: MOLECULAR CELL; v. 81, n. 7, p. 1469+, APR 1 2021.
• Web of Science Citations: 1

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 B-high, perforin(h)(ig)(h) effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response. (AU)

• FAPESP's process: 17/03019-5 - Characterization of antigen-specific CD8+ T cells response after in vivo treatment with 5-aza-2'-deoxycytidine.
• Grantee: Felipe Campos de Almeida
• Support type: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 15/25699-2 - Evaluation of the in vivo treatment with DNA demethylating agents on the development and effector function of CD8T cells
• Grantee: Felipe Campos de Almeida
• Support type: Scholarships in Brazil - Master