Abstract A041: LAG-3 is associated with poor prognosis and LAG-3 blockade enhances the efficacy of PD-1 blockade combined with radiation therapy in breast cancer

Abstract Lymphocyte-activation gene 3 (LAG-3) is an inhibitory receptor expressed on exhausted CD8+ T cells and regulatory T cells (Tregs), and its blockade has been shown to enhance the anti-tumor effects of PD-1 blockade. Transcriptomic and clinical analysis of the METABRIC breast cancer cohort revealed that high LAG-3 expression was correlated with worse relapse-free and overall survival. Furthermore, radiation therapy (RT) improved survival outcomes only in patients with low LAG-3 expression not in patients with high LAG-3 expression. High LAG-3 expression was correlated with increased Treg abundance. In a 4T1 murine breast cancer model, RT combined with PD-1 blockade increased the proportion of LAG-3+ CD8+ T cells and Tregs, particularly in the tumor and spleen. These findings suggested that LAG-3 may mediate therapeutic resistance of RT combined with PD-1 blockade by expanding suppressive T-cell populations. Based on these, we hypothesized that LAG-3 blockade could restore anti-tumor immune response and enhance the therapeutic efficacy of RT combined with PD-1 blockade. Triple combination therapy (TCT) with RT, PD-1 blockade, and LAG-3 blockade delayed tumor growth in both irradiated and unirradiated tumors, reduced lung metastases, and improved survival. TCT significantly increased tumor-specific CD8+ T cells and memory T cells, reduced Tregs, and expanded activated natural killer cells. Mice achieving complete response following TCT rejected tumor rechallenge suggesting the tumor-specific memory response. Taken together, LAG-3 blockade might be a viable approach to optimize the therapeutic efficacy of RT combined with PD-1 blockade. This work was supported by grants from the National Research Foundation of Korea (NRF-2023R1A2C3003782). Citation Format: In Ah Kim, Yoomin Kim, Seung Hyuck Jeon. LAG-3 is associated with poor prognosis and LAG-3 blockade enhances the efficacy of PD-1 blockade combined with radiation therapy in breast cancer [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A041.