Abstract P3-07-24: Role of tumor cell-derived lactic acid in the PD-1/PD-L1 blockade resistant tumor

Abstract Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis (PD-1/PD-L1 blockade therapy) has shown remarkable clinical impact in multiple cancer types. Despite the recent success of PD-1/PD-L1 blockade therapy, acquired resistance, emerging as late relapses or recurrences, has been reported in the long-term follow-up of clinical trials. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. In particular, glycolytic metabolites, such as glucose and lactate, regulate T cell proliferation and function. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts the therapeutic efficacy of, and resistance to, PD-1/PD-L1 blockade therapy. Here, we found that increased lactic acid functionally contributes to an immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade therapy resistant tumors through decreasing PD-L1 and PD-L1 antibody interaction. Furthermore, combinating PD-L1 targeting with our PD-L1-antibody-drug conjugate (ADC) and reducing lactic acid by an MCT-1 inhibitor, AZD3965, within the tumor microenvironment effectively eradicated the resistant tumor cells. Together, our results suggest a new combination treatment strategy to improve the therapeutic efficacy of immune checkpoint blockade therapies Citation Format: Wonkyung Oh, Seung-Oe Lim. Role of tumor cell-derived lactic acid in the PD-1/PD-L1 blockade resistant tumor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-24.