Genome-wide gain-of-function screening characterized lncRNA regulators for tumor immune response

Abstract

The majority of lncRNAs’ roles in tumor immunology remain elusive. This project performed a CRISPR activation screening of 9744 lncRNAs in melanoma cells cocultured with human CD8 + T cells. We identified 16 lncRNAs potentially regulating tumor immune response. Further integrative analysis using tumor immunogenomics data revealed that IL10RB-DT and LINC01198 are significantly correlated with tumor immune response and survival in melanoma and breast cancer. Specifically, IL10RB-DT suppresses CD8 + T cells activation via inhibiting IFN-γ–JAK–STAT1 signaling and antigen presentation in melanoma and breast cancer cells. On the other hand, LINC01198 ’s up-regulation sensitizes the killing of tumor cells by CD8 + T cells. Mechanistically, LINC01198 interacts and activates NF-κB component p65 to trigger the type I and type II interferon responses in melanoma and breast cancer cells. Our study systematically characterized novel lncRNAs involved in tumor immune response.

Disulfidptosis-related lncRNA signature reveals immune microenvironment and novel molecular subtyping of stomach adenocarcinoma

“…Currently, there are many drugs targeting immune checkpoints that have shown promising results in clinical treatment of some STAD patients [ 36 ]. However, they are still ineffective for many patients [ 37 ]. We found that all immune checkpoint genes were upregulated in the high-risk group, indicating immune suppression and decreased immune response against tumors in these patients.…”

The role of mitochondria-related lncRNAs in characterizing the immune landscape and supervising the prognosis of osteosarcoma

“…Another study illustrated that IL10RB-DT was overexpressed in clear cell renal cell carcinoma, especially in advanced T stages [103] . Yang et al proposed that IL10RB-DT inhibited tumor antigen presentation and induced CD8 + T-cell depletion to suppress tumor immune responses, which was strongly negatively associated with the clinical efficacy of ICB and survival in melanoma and breast cancer [104] . Consistent with the results of Zhang et al [105] , we demonstrated that IL10RB-DT was downregulated in MG63, U2OS, and MNNG/HOS.…”

The current advances of lncRNAs in breast cancer immunobiology research

“…Specifically, the activation of LINC01198 promotes the expression of CXCL10, IFN-β, type I IFN receptors, interferon-stimulated genes (ISGs), and the transcriptional activity of NFκB (related to p65 component) in vitro ( Figure 1 ). Equally important, the high expression of LINC01198 is associated with a high score of CD8, IL-2, IL-8, and IL-12 immune signatures and improved OS in BC patients, indicating that LINC01198 is a promoter of IFN-related antitumoral immune response ( 67 ).…”

“…They found that the activation of this lncRNA inhibits the transcription of MHC-I and antigen-processing genes in BC cells. Equally important, the IL10RB-DT expression is associated with poor survival in BC patients ( 67 ). A study about the LINC00624 expression showed that this lncRNA negatively correlates with type I IFN and antigen processing and presentation pathways in vitro .…”

“…Notably, a comprehensive study used ASOs to target LINC00624 in HER2+ BC, resulting in the inhibition of proliferation in vitro and increasing the expression of innate immune response-related genes in xenograft tumor models, supporting the role of LINC00624 as an inhibitor of the antitumoral immune response ( 76 ). In addition, a CRISPR activation screening strategy was recently used to determine the mechanistic role of LINC01198 and IL10RB-DT in BC cells, concluding an association with promoting and suppressing the antitumoral immune response, respectively ( 67 ). These findings highlight lncRNAs as attractive targets for BC immunotherapy.…”