Targeting DNMT1 augments anti-tumor CD8⁺ T cell function

Area of Science:

• Immunology
• Cancer Biology
• Epigenetics

Background:

• Chronic stimulation in the tumor microenvironment (TME) leads to CD8+ T cell exhaustion, a state of dysfunction impacting anti-tumor immunity.
• Exhaustion is linked to stable epigenetic alterations, limiting therapeutic restoration of T cell function, even with immune checkpoint inhibition (ICI).

Purpose of the Study:

• To investigate DNA methyltransferase 1 inhibition (DNMT1i) as a strategy to counteract CD8+ T cell exhaustion and enhance anti-tumor responses.
• To determine if DNMT1i can restore effector function in exhausted CD8+ T cells and synergize with ICI.

Main Methods:

• Utilized a melanoma model to assess the effects of DNMT1i on chronically stimulated CD8+ T cells.
• Analyzed transcriptional and epigenetic changes, including chromatin accessibility, in exhausted T cells.
• Evaluated the function of patient-derived tumor-infiltrating lymphocytes (TILs) after ex vivo expansion with DNMT1i.

Main Results:

• DNMT1i synergized with ICI to restore tumor cell killing activity in exhausted CD8+ T cells.
• DNMT1i reversed exhaustion-associated transcriptional profiles and induced an effector program.
• DNMT1i attenuated global chromatin accessibility changes and facilitated epigenetic remodeling.
• DNMT1i enhanced effector function in melanoma patient-derived TILs.

Conclusions:

• DNMT1 inhibition is a viable strategy to combat CD8+ T cell exhaustion.
• Targeting DNMT1 can restore anti-tumor immunity and potentiate the efficacy of immune checkpoint inhibitors.