Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression

Abstract

The mechanisms through which tumor cells genetically lose antigenicity and evade immune checkpoints remain largely elusive. Here, we report that tissue-specific expression of the human long-noncoding RNA LINK-A in mouse mammary glands initiated metastatic mammary gland tumors, which phenotypically resembled human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein–coupled receptor (GPCR) pathways, attenuating protein kinase A (PKA)-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48–polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A-locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb, and p53, and sensitized mammary gland tumors to immune checkpoint blockers (ICBs). Importantly, PD-1 blockade-resistant TNBC patients exhibited elevated LINK-A levels and downregulated PLC components. Hence, we demonstrated lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which may provide the basis for developing a therapeutic regimen of combinational immunotherapy and effective early prevention for TNBCs.

Long Non-coding RNAs: Emerging Roles in the Immunosuppressive Tumor Microenvironment

“…LncRNAs target the immune checkpoints and cytokines and promote the formation of the immunosuppressive microenvironment, which contributes to tumor progression and drug resistance. Specifically, lncRNAs are emerging new therapeutic targets and prognostic biomarkers for tissue-and clinical stage-specific cancers (26,27).…”

“…For example, Lnc-BM (a lncRNA related to breast cancer brain metastasis), binds to JAK2 and modulates its kinase activity through the Lnc-BM/JAK2/STAT3/ICAM1 pathway (35). Similarly, long intergenic non-coding RNA for kinase activation (LINK-A), interacts with PtdIns(3,4,5) P3 and affects the activation of the AKT pathway in the breast cancer cells (26). LncRNAs play a critical role in the epigenetic and transcriptional regulation of gene expression by interacting with the chromatin (complexes that contain proteins and DNA molecules) within the nucleus.…”

“…Additionally, LINK-A can predict poor prognosis in patients with breast cancers (83,84). Hu et al demonstrated that the expression of LINK-A was negatively associated with the abundance of APCs and CD8 + T cells in the basal-like breast cancers, which indicated a correlation between LINK-A and immunosuppression (26). In the transgenic MMTV-Tg (LINK-A) mouse model, LINK-A functions as an oncogenic lncRNA and initiate metastatic mammary gland tumors, which phenotypically resembled the human TNBC.…”

“…In the transgenic MMTV-Tg (LINK-A) mouse model, LINK-A functions as an oncogenic lncRNA and initiate metastatic mammary gland tumors, which phenotypically resembled the human TNBC. Moreover, LINK-A could enhance the polyubiquitination-mediated degradation of the PLC components and tumor suppressors (Rb and p53) through the inhibitory GPCRs/PKA pathway (26). Treatment with the locked nucleic acids (LNAs) of LINK-A or GPCR antagonists in vivo increased the stability of MHC class I complexes and PLC components.…”

“…Furthermore, lncRNAs involved in the regulation of antigen presentation may potentially serve as therapeutic targets in tumor vaccines. In the mouse models of breast cancer, LINK-A expression was induced in mammary gland tumors (26). The inhibition of LINK-A expression suppressed the tumor progression.…”