Alveolar macrophages (AMs) are a tissue-resident population of particular interest to the field of tumor immunology given the frequency of metastasis to the lung. However, the transcriptional regulators of AM's function in cancer metastasis remain to be fully defined. We demonstrated that: 1) enhanced β-catenin in AMs heightened lung metastasis; 2) β-catenin activity in AMs drove a dysregulated inflammatory program strongly associated with Tnf expression; and 3) localized TNF-α blockade via monoclonal antibodies abrogated this pro-metastatic effect. Lastly, CTNNB1 and TNF expression were positively correlated in the AMs of cancer patients. Overall, our findings revealed a novel Wnt/β-catenin-TNF-α pro-metastatic axis. Given the expansion of Wnt/β-catenin-targeted clinical trials in oncology, we believe our work is a timely and significant advance in the field; demonstrating a novel mechanism and therapeutic approach for targeting products of this pathway in AM-solid tumor biology.

Scott Abrams, PhD