The generation of cancer-specific ribosomes by the lncRNA LISR suppresses melanoma anti-tumour immunity

Gains of chromosome 12p11.21, encoding for the cancer-specific lncRNA LISR, correlate with poor survival in the PanCancer Atlas. In melanoma, LISR is highly expressed by patients resistant to immunotherapy and it contributes to the generation of drug-tolerant persister cells by activating an immune suppressive translational program affecting the synthesis of PD-L1 and of the glycocalyx. Interestingly, the use of glycans to evade the immune system is a characteristic of the sperm. Accordingly, a defective glycocalyx assembly during spermatogenesis causes infertility. Here we show that LISR affects the core ribosome composition and recruits Deleted in AZoospermia Associated Protein 1 (DAZAP1) to regulate an immune suppressive translational program that includes PD-L1 and several glycosylases. Consequently, down-regulation of LISR leads to robust anti-tumour immune responses and re-sensitizes to immune checkpoint blockade. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based cancer-specific strategy to overcome intrinsic resistance to immune checkpoint +blockade.