Bone marrow infiltrated Lnc-INSR induced suppressive immune microenvironment in pediatric acute lymphoblastic leukemia

Immune escape due to immunosuppressive microenvironments, such as those associated with regulatory T (Treg) cells is highly associated with initial occurrence and development of solid tumors or hematologic malignancies. Here, we employed high-throughput transcriptome screening to demonstrate immunosuppression-associated increases in the long noncoding (Inc) RNA Inc-insulin receptor precursor (INSR), which was corrected with INSR expression in CD4 + T cells extracted from the bone marrow of patients with childhood acute T lymphoblastic leukemia. Loss-of-function and gain-of-function assays in vitro and in vivo revealed that membrane-localized and cytoplasm-localized Inc-INSR promoted Treg distribution and decreased the percentage of cytotoxic T lymphocytes, which induced tumor growth. Through direct binding with INSR, Inc-INSR blocked the INSR ubiquitination site, causing abnormal activation of INSR and the phosphatidylinositide 3-kinase/AKT-signaling pathway. These results indicated that Inc-INSR might promote immune suppression by enhancing Treg-cell differentiation and serve as valuable therapeutic targets in the immunosuppressive tumor microenvironment.