Knezevic, Z. | bioRxiv Science

bioRxiv2023

The cancer-specific lncRNA LISR customizes ribosomes to suppress anti-tumour immunity

Although immune checkpoint blockade (ICB) has revolutionized cancer treatment, resistance mechanisms limit its clinical benefit. Here we characterise LISRR, a cancer-specific lncRNA highly expressed in melanoma patients refractory to ICB. In cells undergoing (therapeutic) stress, LISRR recruits DAZAP1 (Deleted in AZoospermia Associated Protein 1) to polysomes and drives the assembly of a subset of ribosomes at the endoplasmic reticulum, directing the synthesis of an immunosuppressive translatome. This includes the immune checkpoint PD-L1 and the enzymes necessary for building the glycocalyx, the sugar coat surrounding the cells. Notably, proper glycocalyx assembly is required for spermatozoa immune evasion during fertilization. Accordingly, targeting LISRR activates immune responses and re-sensitizes to ICB in co-culture models, ex vivo in patient explants, and in vivo in humanized patient-derived models. 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 ICB.

cancer biology↗

bioRxiv2020

Activation of the Integrated Stress Response in drug-tolerant melanoma cells confers vulnerability to mitoribosome-targeting antibiotics.

Therapy resistance remains a major clinical challenge for the management of metastatic melanoma. Here we show that activation of the Integrated Stress Response (ISR), which we show is common in drug-tolerant and resistant melanoma, promotes selective synthesis of mitochondrial proteins in the cytosol. Since mitochondrial translation adapts to the influx of nuclear-encoded mitochondrial proteins, ISR activation indirectly enhances mitochondrial translation and makes these cells highly vulnerable to mitochondrial translation inhibitors. Treatment of melanoma with mitoribosome-targeting antibiotics, induces proteotoxic stress and significantly compromises the growth of NRAS-mutant and immunotherapy-resistant skin melanoma as well as uveal melanoma. Additionally, a triple BRAFi/MEKi/Tigecycline combination reduces intratumour heterogeneity by abrogating emergence of dedifferentiated drug-tolerant cells, and delayed or even prevented the development of resistance in BRAFV600E PDX models. Consistently, a melanoma patient exposed to Doxycycline, a mitoribosome-targeting antibiotic commonly used to treat infections, experienced a complete and long-lasting response of a treatment-resistant lesion. SignificanceOur study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy in BRAF-mutant melanoma, and a therapeutic option to target NRAS-driven and immunotherapy-resistant cutaneous melanoma and uveal melanomas.

cancer biology↗