PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• The immune checkpoint receptor PD-1 (Programmed cell death protein 1), encoded by PDCD1, acts as a tumor suppressor in T cells.
• PDCD1 is frequently inactivated in T cell non-Hodgkin lymphomas (T-NHLs), particularly in advanced stages, correlating with poor prognosis.
• The precise mechanisms by which PD-1 signaling suppresses T-NHL remain largely undefined.

Purpose of the Study:

• To elucidate the tumor-suppressive mechanisms of PD-1 signaling in T cell malignancies.
• To investigate the role of PD-1 in regulating cellular metabolism and transcription factors within T-NHLs.
• To identify potential therapeutic vulnerabilities in PDCD1-mutated T-NHLs.

Main Methods:

• Utilized mouse models of T-NHL and analyzed primary patient samples.
• Investigated the impact of PD-1 signaling on cellular energy metabolism, specifically glycolysis.
• Examined the activity of ATP citrate lyase (ACLY) and its downstream effects on transcription factors, including AP-1.
• Assessed the efficacy of pharmacological ACLY inhibition in PD-1-deficient T-NHLs.

Main Results:

• PD-1 signaling was found to restrict glycolytic energy production and acetyl-CoA generation in T cells.
• PD-1 inactivation promotes ATP citrate lyase (ACLY) activity, leading to increased extramitochondrial acetyl-CoA.
• This elevated acetyl-CoA fuels histone acetylation, enhancing the hyperactivity of activating protein 1 (AP-1) transcription factors.
• Pharmacological inhibition of ACLY effectively disrupted aberrant AP-1 signaling and demonstrated toxicity towards PD-1-deficient T-NHLs.

Conclusions:

• PD-1 acts as a critical regulator of T cell metabolism and AP-1 transcription factor activity.
• PDCD1 mutations create genotype-specific vulnerabilities in T-NHL, particularly through the ACLY-AP-1 axis.
• Targeting ACLY represents a promising therapeutic strategy for PD-1-deficient T-cell lymphomas.