Abstract 4857: The role of tumor microenvironment lactic acid in the cancer cell resistance to anti-PD-L1 and anti-PD-1 blockade therapy

Abstract Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis has shown remarkable clinical impact in multiple cancer types. However, despite its recent success, such impact has been shown to be limited to tumors encompassing specific tumor microenvironment characteristics. Furthermore, a significant proportion of initial responders eventually develop resistance. Combining PD-1/PD-L1 blockade with chemotherapy, radiotherapy, or targeted therapy have been suggested to overcome resistance, yet have been shown to be insufficient in fully accounting for resistance. Unlike normal, differentiated cells, most cancer cells produce large amounts of lactic acid. This metabolic property is often referred to as “aerobic glycolysis, ” a well-known metabolic reprogramming of cancer cells to sustain cell proliferation and a hallmark of cancer. Such property as well as others of the altered metabolism of cancer cells and its byproducts affect the anti-tumor immune response. Notably, glycolytic metabolites, such as lactate, regulate T cell proliferation and function. However, the mechanism behind how such metabolic alterations impact the cancer cells’ resistance to PD-1/PD-L1 blockade therapy remains unclear. Thus, we sought to decipher the role of tumor-cell derived lactic acid in PD-1/PD-L1 therapy resistance and propose new immunotherapeutic strategies to improve the efficacy of PD-1/PD-L1 blockade therapies. 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. Altogether, the findings in this study uncover a new mechanism of how lactic acid induces an immunosuppressive tumor microenvironment and suggest a potential combination treatment strategy to overcome the tumor resistance to PD-1/PD-L1 blockade therapy and improve clinical outcomes. Citation Format: Alyssa Kim, Wonkyung Oh, Deepika Dhawan, Deborah W. Knapp, Seung-Oe Lim. The role of tumor microenvironment lactic acid in the cancer cell resistance to anti-PD-L1 and anti-PD-1 blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4857.