Simple Summary Immune checkpoint inhibitors (ICIs) have revolutionized treatment of advanced melanoma and survival of melanoma patients has radically improved since. However, as durable responses... Show moreSimple Summary Immune checkpoint inhibitors (ICIs) have revolutionized treatment of advanced melanoma and survival of melanoma patients has radically improved since. However, as durable responses after ICIs are only observed in 30-50% of melanoma patients, there is an unmet need to identify predictive biomarkers for response. This systematic review demonstrates the substantial number of publications that have studied a wide variety of possible biomarkers. Covering 177 publications that investigated 128 unique biomarkers, we provide an overview of all studied biomarkers in correlation with response or survival. We highlight blood, tumor and fecal biomarkers that were associated with response to ICIs in multiple studies. Of these, only T-cell inflamed gene expression profiling was predictive for response in a large clinical trial and validated in other studies, thus representing a promising biomarker for clinical practice. Large validation studies are warranted to confirm the predictive utility of other biomarkers, thereby further personalizing immunotherapy treatment. Immune checkpoint inhibitors (ICIs) have strongly improved the survival of melanoma patients. However, as durable response to ICIs are only seen in a minority, there is an unmet need to identify biomarkers that predict response. Therefore, we provide a systematic review that evaluates all biomarkers studied in association with outcomes of melanoma patients receiving ICIs. We searched Pubmed, COCHRANE Library, Embase, Emcare, and Web of Science for relevant articles that were published before June 2020 and studied blood, tumor, or fecal biomarkers that predicted response or survival in melanoma patients treated with ICIs. Of the 2536 identified reports, 177 were included in our review. Risk of bias was high in 40%, moderate in 50% and low in 10% of all studies. Biomarkers that correlated with response were myeloid-derived suppressor cells (MDSCs), circulating tumor cells (CTCs), CD8+ memory T-cells, T-cell receptor (TCR) diversity, tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP), and a favorable gut microbiome. This review shows that biomarkers for ICIs in melanoma patients are widely studied, but heterogeneity between studies is high, average sample sizes are low, and validation is often lacking. Future studies are needed to further investigate the predictive utility of some promising candidate biomarkers. Show less
