Kaczanowska and Beury et al. focused on the premetastatic niche microenvironment that forms prior to detectable metastasis. In a rhabdomyosarcoma model, which forms lung mets, analysis of pre-metastatic lungs in tumor-bearing mice identified a myeloid cell-rich immune suppression gene signature. Myeloid cells engineered to deliver IL-12 (IL-12-GEMys) infiltrated metastatic sites and reversed the immune suppression signature, resulting in increased activated T and NK cells, with improved survival and decreased lung mets in tumor-bearing mice. IL-12-GEMy treatment was CD8+ T cell-dependent and was enhanced by chemotherapy, producing durable cures.
Contributed by Katherine Turner
ABSTRACT: Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.