Fusion of Invasive Tumor Cells with Infiltrating Macrophages Fuels Epithelial-Mesenchymal Transition and Adaptive Immune Evasion

Abstract

Heterotypic interaction between tumor cells and adjacent stromal cells mediates tumor development. However, how tumor heterogeneity commits tumors to the malignant transformation and evasion of immunity against metastasis is poorly understood. Here, we have investigated the fusogenicity of human invasive glioblastoma, triple negative breast cancer and gallbladder cancer cells that are all characterized by mesenchymal cell plasticity. These cells displayed the rigorous ability to fuse with macrophages and augment epithelial-mesenchymal transition (EMT), transforming the fused cells into highly invasive hybrids. YKL-40 (Chitinase-3-like-1), known to promote inflammation and serve as an EMT marker, was essential and sufficient for both cell fusion and the invasiveness of tumor cells that express EMT and tumor-associated macrophage markers. Intriguingly, differential gene profiling of single clones from the hybrids demonstrated that YKL-40 and immune checkpoint protein B7-2 (CD86) were elevated and functioned to independently suppress anti-tumor immune factor levels of CD8 + -cytotoxic T lymphocytes (CTL); thus resulting in escape of immune surveillance. YKL-40 and B7-2 dual shRNA abrogated YKL-40-mediated cell fusion and restored CTL anti-tumor immunity, compromising tumor development in xenografts. Clinically, we found tumor hybrids were present in mesenchymal types of glioblastoma, gallbladder cancer and breast cancer. In addition, YKL-40 expression in glioblastoma was correlated with decreased disease-free survival in patients. Collectively, these data offer novel cellular and molecular mechanisms underpinning immune evasion and tumor malignancy, and suggest a new immunotherapeutic intervention strategy by targeting both YKL-40 and B7-2 in cancer.