3081 - LAG-3 Blockade Enhances the Anti-Tumor Efficacy of PD-1 Blockade Combined with Radiotherapy in a Syngeneic Murine Triple-Negative Breast Cancer Model
Presenter(s)
Y. Kim1, S. H. Jeon2, N. Park3, S. Kim1, and I. A. Kim4; 1Department of Tumor Biology, Seoul National University Graduate School of Medicine, Seoul, Korea, Republic of (South), 2Seoul National University Bundang Hospital, Seongnam, Korea, Republic of (South), 3Seoul National University, Seoul, Korea, Republic of (South), 4Department of Radiation Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea, Republic of (South)
Purpose/Objective(s): The anti-tumor efficacy of PD-1 blockade and local radiotherapy (RT) is often limited by diverse mechanisms that suppress CD8+ T cell responses. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory receptor expressed on various immune cells, including exhausted CD8+ T cells, Tregs, and natural killer (NK) cells. Activation of LAG-3 signaling suppresses CD8+ T cells and NK cells, while enhancing the immunosuppressive function of Tregs 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. Therefore, we hypothesized that combining LAG-3 blockade with PD-1 blockade and local RT would overcome treatment resistance in triple-negative breast cancer (TNBC).
Materials/Methods: The 4T1 syngenic murine triple-negative breast cancer (TNBC) model was utilized to evaluate the efficacy of LAG-3 blockade in combination with PD-1 blockade and RT. T cells in tumors, tumor-draining lymph nodes (TdLNs), and spleen were analyzed to assess the antitumor immune responses upon the treatments. Multi-color flow cytometry, immunohistochemorty, and multiplex immunoassay were performed to evaluate immune response of each treatment.
Results: Triple combination of RT, PD-1 blockade and LAG-3 blockade resulted in the greatest tumor growth delay in both irradiated (primary) and unirradiated (secondary) tumors, with a significant reduction in metastatic lung nodules. The proportion of tumor-infiltrating CD8+ T cells increased with triple combination therapy while the proportion of Tregs decreased in both primary and secondary tumors compared to the PD-1 plus RT. Interestingly, the proportions of CD8+ T cells, as well as CD4+ T cells, with an effector memory phenotype in spleen were most significantly elevated by the triple combination therapy. In tumor-draining lymph nodes, the proportion of conventional type 1 dendritic cells capable of antigen cross-presentation to CD8+ T cells was significantly increased by the triple combination therapy. Moreover, the cytokine production by NK cells in spleen was enhanced, and cytotoxic NK cells in tumor microenvironment were increased following triple combination therapy.
Conclusion: These findings suggest that LAG-3 blockade enhances the therapeutic efficacy of local RT and PD-1 blockade by promoting T cell–mediated anti-tumor immune responses. Therefore, LAG-3 blockade combined with RT and PD-1 blockades and could be a viable strategy for the treatment of TNBC.