Multi-omics Characterization of Response to PD-1 Inhibitors in Advanced Melanoma

Simple Summary The survival of advanced melanoma patients has been improved in recent years due to immunotherapy. However, not all patients respond to this treatment. For this reason, it is necessary to know the mechanisms of the response and resistance to immunotherapy. In this work, clinical samples from advanced melanoma patients treated with immunotherapy were analyzed. The obtained results suggested that the proteins involved in protein processing in the endoplasmic reticulum and antigen presentation, as well as the immune and inflammatory responses, play a role in the response to immunotherapy. Additionally, we built a prognostic signature capable of identifying those patients that will respond to immunotherapy. The study of the mechanisms of the resistance and response to immunotherapy could help in the definition of new therapies for these patients that do not respond to immunotherapy.Abstract Immunotherapy improves the survival of patients with advanced melanoma, 40% of whom become long-term responders. However, not all patients respond to immunotherapy. Further knowledge of the processes involved in the response and resistance to immunotherapy is still needed. In this study, clinical paraffin samples from fifty-two advanced melanoma patients treated with anti-PD-1 inhibitors were assessed via high-throughput proteomics and RNA-seq. The obtained proteomics and transcriptomics data were analyzed using multi-omics network analyses based on probabilistic graphical models to identify those biological processes involved in the response to immunotherapy. Additionally, proteins related to overall survival were studied. The activity of the node formed by the proteins involved in protein processing in the endoplasmic reticulum and antigen presentation machinery was higher in responders compared to non-responders; the activity of the immune and inflammatory response node was also higher in those with complete or partial responses. A predictor for overall survival based on two proteins (AMBP and PDSM5) was defined. In summary, the response to anti-PD-1 therapy in advanced melanoma is related to protein processing in the endoplasmic reticulum, and also to genes involved in the immune and inflammatory responses. Finally, a two-protein predictor can define survival in advanced disease. The molecular characterization of the mechanisms involved in the response and resistance to immunotherapy in melanoma leads the way to establishing therapeutic alternatives for patients who will not respond to this treatment.