Circulatory plasma proteomic biomarkers combined with high-throughput proteomic screen of patient-derived organotypic tumor spheroids predict responses to immunotherapy in melanoma patients 3207

Description The majority of patients treated with immune checkpoint blockade (ICB) do not have durable responses underscoring a need to identify biomarkers for patient stratification. Here, we performed plasma proteomic analysis of > 700 proteins on 174 metastatic melanoma patients treated with ICB and then expanding our analysis to a larger cohort of 250 patients exploring baseline and early on-treatment predictive biomarkers. Based on differentially expressed proteins we identified a co-regulated module of proteins associated with resistance including IL-6, IL-8, MIA, LIF and GDF-15 that outperforms several tissue-based approaches as predictor for ICB outcome. By analyzing a mix of single-cell and bulk RNA-sequencing data of tumor biopsies from 102 patients, we determined the relative contribution of cells in the tumor and associated plasma protein levels with tumor immune microenvironment (TME) phenotypes. The major TME subsets driving the expression of the non-response module proteins were tumor and myeloid cells. Lastly, we performed a secretome analysis obtained from patient-derived organotypic tumor spheroids treated with ICB to validate biomarkers and better characterize actionable biology of melanoma resistance. In summary, our integrated longitudinal analyses of circulatory plasma proteins, combined with TME transcriptomics, provides novel insights into the biology of ICB resistance, demonstrates prognostic significance and utility of plasma proteomics in biomarker discovery. Topic Categories Immune Mechanisms of Human Disease (HUM)