Genetically Engineered Myeloid Cells Rebalance the Core Regulatory Immune Suppression Program in Metastasis

Abstract

Abstract Tumor metastasis is a critical step in the progression of solid tumors that is associated with patient mortality, yet we have limited knowledge of the metastatic microenvironment to effectively target this process. The pre-metastatic niche is the tumor-promoting microenvironment that is established at distant sites in response to primary tumor growth before detectable metastatic disease. We characterized immune populations in the lungs of tumor-bearing mice by flow cytometry and RNA sequencing approaches. We identified an immune suppression gene signature in pre-metastatic niche formation that is found predominantly within myeloid cells. In addition to the increase of myeloid cells and immunosuppressive pathways, we discovered that T cell populations are reduced in pre-metastatic lungs. We hypothesized that reversing this immunosuppressive environment would restore T cell function and antitumor immunity. We designed a novel approach in which we generated Genetically-Engineered Myeloid cells (GEMys) to deliver IL-12, a potent antitumor molecule, into the pre-metastatic microenvironment. We evaluated the lungs by flow cytometry and observed that IL12-GEMy-treated mice had increased numbers of T cells and enhanced expression of activation markers, resulting in reduced metastasis and increased survival. When combined with chemotherapy pre-conditioning, IL12-GEMys cured mice of established tumors and generated long-lived T cell memory, as these mice were immune to subsequent tumor challenge. These studies 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.