Harnessing neutrophils to prevent metastasis 3826

Abstract Description Metastatic disease accounts for the majority of cancer-related deaths. The seeding and growth of metastases are often bolstered by the activity of neutrophils, which secrete pro-tumor factors and suppress T cell responses. Conversely, neutrophils are also critical responders to acute damage and infection. To harness the therapeutic potential of neutrophils, we developed a neutrophil-activating therapy (NAT) that consists of intratumorally administered anti-tumor antibody, anti-CD40 agonist antibody, and tumor necrosis factor. This therapy clears primary tumors in a T cell-independent manner and induces a tumor-specific T cell memory response (Linde et al., Cancer Cell 2023). Surprisingly, NAT reduces distant lung metastasis in several mouse models. Cell-type specific knockout and depletion experiments revealed that neutrophils are responsible for this anti-metastatic effect during the first week after treatment; flow cytometry analysis of NAT-treated mice reveals significant influx of activated CD8 T cells into lungs 9 days post-treatment. Together this suggests that NAT induces a temporally coordinated response between neutrophils and T cells to protect mice from distant metastases. NAT also reduces metastases when delivered subcutaneously, showing promise as an off-the-shelf immunotherapy that can prevent metastases for a range of cancers, potentially as a neoadjuvant therapy Funding Sources Supported by NIH R01 CA251174; U54 CA274511; Stanford Graduate Fellowship; Stanford Biosciences Program. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)