Cancer-educated mesenchymal stem cells promote the survival of cancer cells at primary and distant metastatic sites via the expansion of bone marrow-derived-PMN-MDSCs

Abstract

AbstractBone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that can differentiate into a variety of cell types. BMSCs are chemotactically guided towards the cancer cells and contribute to the formation of a cancer microenvironment. The homing of BMSCs was affected by various factors. Disseminated tumour cells (DTCs) in distant organs, especially in the bone marrow, are the source of cancer metastasis and cancer relapse. DTC survival is also determined by the microenvironment. Here we aim to elucidate how cancer-educated BMSCs promote the survival of cancer cells at primary tumour sites and distant sites. We highlight the dynamic change by identifying different gene expression signatures in intratumoral BMSCs and in BMSCs that move back in the bone marrow. Intratumoral BMSCs acquire high mobility and displayed immunosuppressive effects. Intratumoral BMSCs that ultimately home to the bone marrow exhibit a strong immunosuppressive function. Cancer-educated BMSCs promote the survival of lung cancer cells via expansion of MDSCs in bone marrow, primary tumour sites and metastatic sites. These Ly6G+ MDSCs suppress proliferation of T cells. CXCL5, nitric oxide and GM-CSF produced by cancer-educated BMSCs contribute to the formation of malignant microenvironments. Treatment with CXCL5 antibody, the iNOS inhibitor 1400w and GM-CSF antibody reduced MDSC expansion in the bone marrow, primary tumour sites and metastatic sites, and promoted the efficiency of PD-L1 antibody. Our study reveals that cancer-educated BMSCs are the component of the niche for primary lung cancer cells and DTCs, and that they can be the target for immunotherapy.