METTL14 Enhances Antitumor Immunity through m6A-Dependent Loss of PD-1

Area of Science:

• Immunology
• Epigenetics
• Molecular Biology

Background:

• N6-methyladenosine (m6A) is a crucial epitranscriptomic modification influencing gene expression and immune responses.
• Programmed cell death-1 (PD-1) is a key immune checkpoint receptor that regulates T cell activity and is a target for cancer immunotherapy.

Purpose of the Study:

• To investigate the role of m6A modification in regulating PDCD1 (PD-1) gene expression and its impact on T cell function.
• To explore the potential of targeting the m6A-PDCD1 axis for improving cancer immunotherapy.

Main Methods:

• Analysis of m6A modification on PDCD1 mRNA in T cells.
• Investigating the role of METTL14, YTHDF1/2/3 in PDCD1 mRNA destabilization.
• Assessing the effect of METTL14 deficiency on CD8+ T cell activation and tumor growth in mouse models.
• Correlating METTL14 and PDCD1 levels with clinical cancer data and immunotherapy response.
• Evaluating the combination of a METTL3-METTL14 complex degrader (WD6305) with anti-PD-1 therapy in vivo.

Main Results:

• PDCD1 gene expression is regulated by m6A modification in T cells.
• METTL14 promotes m6A-dependent destabilization of PDCD1 mRNA via YTHDF1/2/3, leading to PDCD1 downregulation.
• METTL14 deficiency impairs CD8+ T cell activation and enhances tumor growth due to elevated PD-1 levels.
• Clinical data show a negative association between METTL14 and PDCD1 levels, correlating with resistance to PD-1 immunotherapy.
• Combined WD6305 and anti-PD-1 therapy suppressed tumor growth in mice.

Conclusions:

• m6A modification of PDCD1 represents a novel immunoregulatory mechanism impacting T cell function and tumor immunity.
• Targeting the m6A-PDCD1 axis, particularly through METTL14 modulation or combined therapies, offers a promising strategy to enhance anti-PD-1 cancer immunotherapy efficacy.