Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells

Abstract

Recent studies have demonstrated abundant transcription of a set of noncoding RNAs (ncRNAs) preferentially within tumors as opposed to normal tissue. Using an approach from statistical physics, we quantify global transcriptome-wide motif use for the first time, to our knowledge, in human and murine ncRNAs, determining that most have motif use consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs, typically of recent evolutionary origin, has motif use that is often indicative of pathogenassociated RNA. For instance, we show that the tumor-associated human repeat human satellite repeat II (HSATII) is enriched in motifs containing CpG dinucleotides in AU-rich contexts that most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNAs functions as immunostimulatory "self-agonists" and directly activates cells of the mononuclear phagocytic system to produce proinflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We propose that the innate response in tumors may partially originate from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors, and thereby assign a previously unidentified danger-associated function to a set of dark matter repetitive elements. These findings potentially reconcile several observations concerning the role of ncRNA expression in cancers and their relationship to the tumor microenvironment.noncoding RNA | genome evolution | cancer immunology

Diverse repetitive element RNA expression defines epigenetic and immunologic features of colon cancer

“…However, repeat RNAs appear to have direct cellular effects aside from being substrates for retrotransposition. Recently, a variety of repeat RNAs have been shown to activate the innate immune response through the pattern recognition receptor pathways (8,9,14,15). The expression of these repeats appears to be a combination of p53 function and DNA CpG methylation in model organisms (14,16).…”

Pericentromeric satellite repeat expansions through RNA-derived DNA intermediates in cancer

“…S7E). Beyond their potential contribution to the viability of proliferating cancer cells, HSATII transcripts may also play a role in shaping tumorhost interactions, as shown in the accompanying paper (33). Thus, the disruption of HSATII RT may have direct effects on cancer cells, as well as modulating the immune response against tumor cells.…”

A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy

“…The fitness effects of these interactions have a specific interpretation: they capture neoantigen “non-selfness”. Our model formalizes what makes a tumor immunologically different from its host, analogously to models for innate recognition of non-self nucleic acids 25 .…”