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Mol. Ther., December 31, 2024 | https://doi.org/10.1016/j.ymthe.2024.12.044 Tumor cell-derived lactic acid inhibits the interaction between PD-L1 protein and PD-L1 antibody in the PD-1/PD-L1 blockade therapy-resistant tumor

Wonkyung Oh ^{1 5}, Alyssa Min Jung Kim ^{1 5}, Deepika Dhawan ², Deborah W. Knapp ^{2 3}, Seung-Oe Lim^{1 3 4 *}

¹Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
²Department of Veterinary Clinical Science, Purdue University, West Lafayette, IN 47907, USA
³Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
⁴Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
⁵These authors contributed equally.

^*Corresponding author: correspondence to Seung-Oe Lim

Abstract

Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis has shown remarkable clinical impact in multiple cancer types. Nonetheless, despite the recent success of PD-1/PD-L1 blockade therapy, such response rates in cancer patients have been limited to tumors encompassing specific tumor microenvironment characteristics. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts their resistance to PD-1/PD-L1 blockade therapy. Here, we found that tumor cell-derived lactic acid renders the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade-resistant tumors by inhibiting the interaction between the PD-L1 protein and anti-PD-L1 antibody. Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. The findings of this study provide a new mechanism of how lactic acid induces an immunosuppressive tumor microenvironment and suggest a potential combination treatment to overcome the tumor resistance to PD-1/PD-L1 blockade therapy.

논문정보

형식Research article
게재일2025년 12월 (BRIC 등록일 2025-01-02)
연구진국외 연구진
분야 생명과학 > 노화/암생물학

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