Related Experiment Video

Updated: May 9, 2025

Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
07:04

Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology

Published on: May 2, 2025

151

Lactic acid inhibits the interaction between PD-L1 protein and PD-L1 antibody in the PD-1/PD-L1 blockade

Wonkyung Oh1, Alyssa Min Jung Kim1, Deepika Dhawan2

  • 1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|May 1, 2025
PubMed

Insights

Tumor cell lactic acid creates an immunosuppressive environment, hindering programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy. Combining PD-L1 antibody-drug conjugates with lactic acid reduction effectively treats resistant tumors.

Area of Science:

  • Immunology
  • Cancer Biology
  • Metabolic Pathways

Background:

  • Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis offer significant clinical benefits in various cancers.
  • However, response rates are limited in tumors with specific microenvironment characteristics.
  • The impact of cancer cell metabolic alterations on resistance to PD-1/PD-L1 blockade remains largely unexplored.

Purpose of the Study:

  • To elucidate the mechanism by which cancer cell metabolic activity influences resistance to PD-1/PD-L1 blockade therapy.
  • To identify novel therapeutic strategies to overcome resistance to PD-1/PD-L1 blockade.

Main Methods:

  • Investigated the role of tumor cell-derived lactic acid in shaping the tumor microenvironment.
  • Assessed the efficacy of combining PD-L1 antibody-drug conjugate (PD-L1-ADC) therapy with a monocarboxylate transporter 1 (MCT-1) inhibitor (AZD3965).

Main Results:

  • Tumor cell-derived lactic acid was found to induce an immunosuppressive tumor microenvironment.
  • Lactic acid inhibits the binding of anti-PD-L1 antibodies to PD-L1, contributing to resistance.
  • Combination therapy with PD-L1-ADC and AZD3965 demonstrated efficacy in treating PD-1/PD-L1 blockade-resistant tumors.

Conclusions:

  • Lactic acid promotes tumor resistance to PD-1/PD-L1 blockade by creating an immunosuppressive microenvironment.
  • Targeting lactic acid metabolism in conjunction with PD-L1 blockade presents a promising therapeutic approach for resistant cancers.
Keywords:
PD-L1PD-l/PD-L1 blockade therapyantibodyantibody-drug conjugateimmunotherapylactic acidresistancetumor microenvironment

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