The cancer-specific lncRNALISRcustomizes ribosomes to suppress anti-tumour immunity

AbstractResponses to anticancer therapies in patients with advanced metastatic disease are often lower than 50% and the majority of patients initially responding develop resistance later on. Therapy resistance often follows an adaptation phase in which cancer cells exit the cell cycle and engage the Integrated Stress Response (ISR). Activation of this pathway induces the emergence of drug-tolerant persister cells via the block of CAP-dependent translation while enhancing translation of select mRNAs that support survival, migration and dampen immunogenicity. Little is known about the molecular mechanisms underlying ISR-dependent immune escape. Searching for transcripts specifically associated with polysomes upon ISR activation we identified the lncRNALISR. We showed that this untranslated transcript, could suppress the production of putative neoantigens, while promoting translation ofPD-L1and other mRNAs involved in the formation of the glycocalyx. Accordingly,LISRlocus is amplified in 60% of melanomas and its expression is increased in patients refractory to Immune Checkpoint Blockade (ICB). Consequently, inhibition ofLISRstimulated anti-tumour immune responses bothin vitroand in humanized and ICB-resistant patient-derived xenografts. This study establishes a link between lncRNAs, translation rewiring in cancer and immunogenicity, and identifies an RNA-based cancer-specific therapeutic strategy to overcome intrinsic resistance to ICB.