Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer

Area of Science:

• Immunology
• Cancer Biology
• Pharmacology

Background:

• Immune checkpoint blockade benefits cancer therapy in limited patient subsets.
• Accumulation of immunosuppressive metabolites like adenosine in tumors hinders anti-cancer immune responses.
• Current strategies targeting adenosine generation and signaling show limited clinical benefit.

Purpose of the Study:

• To investigate the mechanism by which adenosine suppresses anti-cancer T-cell responses.
• To identify and evaluate a novel equilibrative nucleoside transporter 1 (ENT1) antagonist for cancer immunotherapy.
• To assess the efficacy of ENT1 inhibition in combination with anti-PD-1 therapy.

Main Methods:

• Investigated adenosine uptake via ENT1 in T-cells and its effect on pyrimidine nucleotide synthesis.
• Identified EOS301984 as a potent ENT1 antagonist.
• Evaluated EOS301984's ability to restore pyrimidine levels and enhance T-cell responses in vitro.
• Assessed the combination of EOS301984 and anti-PD-1 in a humanized mouse model of triple-negative breast cancer.

Main Results:

• Adenosine suppresses anti-cancer T-cell responses by inhibiting de novo pyrimidine nucleotide synthesis after uptake via ENT1.
• EOS301984 restores pyrimidine levels in T-cells within adenosine-rich tumor environments.
• EOS301984 enhances tumor cell killing by memory T-cells and ex vivo expansion of tumor-infiltrating lymphocytes.
• Combination therapy with EOS301984 and anti-PD-1 demonstrated synergistic tumor growth control in a preclinical model.

Conclusions:

• ENT1 inhibition is a promising strategy to overcome adenosine-mediated immunosuppression in cancer.
• EOS301984 augments anti-cancer immune responses by restoring T-cell pyrimidine synthesis.
• Targeting ENT1 offers a novel approach to enhance the efficacy of cancer immunotherapies like anti-PD-1.