Regulation of T cell differentiation and function by long noncoding RNAs in homeostasis and cancer

Abstract

Long noncoding RNAs (lncRNAs) increase in genomes of complex organisms and represent the largest group of RNA genes transcribed in mammalian cells. Previously considered only transcriptional noise, lncRNAs comprise a heterogeneous class of transcripts that are emerging as critical regulators of T cell-mediated immunity. Here we summarize the lncRNA expression landscape of different T cell subsets and highlight recent advances in the role of lncRNAs in regulating T cell differentiation, function and exhaustion during homeostasis and cancer. We discuss the different molecular mechanisms of lncRNAs and highlight lncRNAs that can serve as novel targets to modulate T cell function or to improve the response to cancer immunotherapies by modulating the immunosuppressive tumor microenvironment.

Keywords: adoptive cell therapy; dysfunction; exhaustion; gamma delta T cell; noncoding RNA; regulatory T cell; tumor immune evasion; tumor-infiltrating T cell.

Figure 1

Expression of lncRNAs in CD4⁺ and CD8⁺ T cell subsets. Cell type-specific and differentiation-specific lncRNAs that modulate CD4⁺ or CD8⁺ T cell function or differentiation during homeostasis, infection and autoimmunity are shown. Th1, CD4⁺ T helper 1 cells; Th2, CD4⁺ T helper 2 cells; Th17, CD4⁺ T helper 17 cells; Treg, regulatory T cells. LncRNAs expressed in humans and mice (bold), lncRNAs expressed solely in mice (*).

Figure 2

Expression of lncRNAs in tumor-infiltrating T cell subsets. The pie chart depicts lncRNAs expressed in tumor-infiltrating T cell subsets and tumor cell-expressed lncRNAs affecting TIL-specific functions (center). Exosome-derived lncRNAs represent a cluster of lncRNAs that are transmitted from exhausted CD8⁺ T cells via exosomes to non-exhausted CD8⁺ T cells (**) (69). LncRNAs expressed in humans and mice are labeled in bold.

Figure 3

Molecular mechanism of selected lncRNAs. (A) LncRNA NKILA: Following T cell activation, IFNγ-JAK-STAT1 signaling triggers NKILA transcription. STAT1-mediated transcription of NKILA is induced by Ca²⁺ influx and activation of calmodulin, which removes HDACs from the promotor. Consequently, NKILA directly interacts with the NFκB-subunit p65 and IκBα, regulating the sensitivity to AICD of Th1 and CD8⁺ T cells. Based on Huang et al. (28). (B) LncRNA EPIC1: EPIC1 together with EZH2 enhances H3K27me3 chromatin modifications at the loci of IFNGR1 and antigen presentation genes, downregulating their transcription. This leads to tumor immune evasion and promotes resistance to immune checkpoint inhibitor therapy by blockage of IFNγ-JAK-STAT1 signaling. Based on Guo et al. (92). (C) LncRNA lnc-EGFR: EGFR is stabilized by the bound lnc-EGFR, thereby blocking its ubiquitination by c-CBL. EGFR activation and signaling via AP-1/NF-AT1 is enhanced, thereby promoting EGFR expression, Treg cell differentiation and tumor progression. Based on Jiang et al. (93).