Immune-Related Adverse Effects (Iraes) Associated Proteomic Profile In Late-Stage Nsclc Patients After Pd-1 Blockade.

Abstract Immune checkpoint inhibitors (ICIs) in cancer therapy have improved clinical responses and overall survival for patients with non-small cell lung cancer (NSCLC). However, their action is quite often correlated with increased amount of immune related adverse effects (irAEs). In severe cases, strict control and prediction of such events is of high importance for proper patient management. Interestingly, low grade irAEs, observed after anti-PD-1 treatment are associated with better overall response rate (ORR) or overall higher survival benefit as previously reported. Therefore, defining good predictors that could address the occurrence of irAEs has been addressed by many researchers and a potential use of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) has been already reported. In this study we have focused on the discovery of plasma based proteomic profiles associated with irAEs occurrence in two cohorts of late stage NSCLC patients receiving PD-1 blockade. Deep, unbiased plasma proteome profiling was achieved using LC-MS/MS in DIA mode (HRM). Proteins from plasma samples were denatured, digested, and injected into Thermo-Fisher instrument. High depth library for DIA approach was generated for protein identification and quantification using Spectronaut 14 (Biognosys). Protein panel selection was done using sPLS-DA approach. Gene ontology enrichment analysis for biological processes was performed on selected proteins. Unbiased analysis of 125 plasma samples from late-stage NSCLC patients treated with anti- PD1 (75 baseline and 50 after 8-weeks treatment) resulted in identification and quantifications of 853 proteins. Progression free survival analysis using Kaplan-Meier estimators showed significant difference between subjects with reported irAEs against those without, within and between both cohorts. Classification analysis using sPLS-DA on 43 subjects (86 of 125 samples) after optimization provided proteomic signature which completely separated patients with and without reported irAEs. Identified proteomic panel was used for hierarchical clustering, confirming separation across all subjects (irrespective of cohort allocation) into two main blocks. Interestingly, subjects divided into both groups showed lack of significance with regards to T cell-monocyte ratio. However, analysis of biological processes present in the panel revealed strong enrichment of proteins involved in immune responses, especially related to B cell activation, regulation and signaling. In this study we confirm prior observations of survival benefit related to irAEs after treatment with PD-1 blockade in late stage NSCLC patients. We also demonstrate the power of deep proteomic profiling in biomarker selection associated to irAEs, allowing for further development of new tools for improved patient management and risk-benefit assessment. Citation Format: Kamil Sklodowski, Vito Dozio, Roberta Poli, Andrés Lanzós, Silvia Lopez-Lastra, Kristina Beeler, Emanuela Romano. Immune-related adverse effects (irAEs) associated proteomic profile in late-stage NSCLC patients after PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1615.