LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion and immunotherapy resistance

Abstract

Through an integrative analysis of the lincRNA expression and tumor immune response in 9,626 tumor samples across 32 cancer types, we developed a lincRNA-based immune response (LIMER) score that can predict the immune cells infiltration and patient prognosis in multiple cancer types. Our analysis also identified tumor-specific lincRNAs, including EPIC1, that potentially regulate tumor immune response in multiple cancer types. Immunocompetent mouse models and in vitro co-culture assays demonstrated that EPIC1 induces tumor immune evasion and resistance to immunotherapy by suppressing tumor cell antigen presentation. Mechanistically, lincRNA EPIC1 interacts with the histone methyltransferase EZH2, leading to the epigenetic silencing of IFNGR1, TAP1/2, ERAP1/2, and MHC-I genes. Genetic and pharmacological inhibition of EZH2 abolish EPIC1’s immune-related oncogenic effect and its suppression of interferon-γ signaling. The EPIC1-EZH2 axis emerges as a potential mechanism for tumor immune evasion that can serve as therapeutic targets for immunotherapy.

Immune-related lincRNA pairs predict prognosis and therapeutic response in hepatocellular carcinoma

“…1 A. First, we selected 454 lincRNAs, which were potential tumor-intrinsic (highly expressed in tumor tissues compared with adjacent normal tissues but not expressed in immune tissues) immune regulators from a previous study 21 . Next, we retrieved the transcriptome profiles of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and separated the data of lncRNA and mRNA using the GENCODE annotation file.…”

“…2 C,D). We applied Spearman’s correlation analysis to the IRLPS risk score and the enrichment scores of 68 immune signatures calculated using the single-sample gene set enrichment analysis (ssGSEA) 21 . Results showed that the risk score was positively associated with neutrophil cells but inversely correlated with cytotoxic T cell, DC cells, and IFN signaling (Fig.…”

Inducing immunogenic cell death in immuno-oncological therapies

“…At the same time, the evolution of the constituent CCs shapes the phenotypic heterogeneity of the tumors in favor of competing for survival and progression under dynamic immune selection pressures. It has been reported that the oncogenic signals may disrupt the expression of cell cycle and antigen presentation genes of host cells, thereby leading to abnormal proliferation of CCs in the body and a state of unresponsiveness to the defense mechanisms, respectively ( 27 , 28 ). CCs can decrease the downstream signal stimulation of the TCR and lead to dysfunction or apoptosis of T cells through the upregulation of the immune-suppressive molecule PD-L1 ( 29 ).…”

MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

“…EZH2 knockdown in mouse models of cancer or targeting EZH2 with specific inhibitors allowed restoration of MHC-I expression in melanoma, B cell lymphoma and lung cancer [43,44,112,113]. Remarkably, some tumors that did not exhibit alterations in EZH2 (i.e., gene amplification/activating mutation) remained sensitive to EZH2 inhibition revealing an alternate regulatory mechanism; a long non-coding (lnc)RNA EPIC1 was found to bind EZH2 leading to the epigenetic silencing of IFNGR1, TAP1/2, ERAP and MHC-I genes [114].…”