Sonia Cinque, Yvessa Verheyden, Vicky Katopodi, Zorica Knezevic, Ewout Demesmaeker, Sara Adnane, Sarah Hanache, Roberto Vendramin, Fabian Stinkens, Felicia Vervloesem, Alessandro Cuomo, Joanna Pozniak, Alvaro Cortes Calabuig, Sebastien Tabruyn, Oliver Bechter, Maria Francesca Baietti, Elisabetta Groaz, Tiziana Bonaldi, Eleonora Leucci
Responses 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 lncRNA LISR. We showed that this untranslated transcript, could suppress the production of putative neoantigens, while promoting translation of PD-L1 and other mRNAs involved in the formation of the glycocalyx. Accordingly, LISR locus is amplified in 60% of melanomas and its expression is increased in patients refractory to Immune Checkpoint Blockade (ICB). Consequently, inhibition of LISR stimulated anti-tumour immune responses both in vitro and 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.