Predicting metastasis in melanoma patients is important for disease management and could help to identify those who might benefit from adjuvant treatment.,The aim of this study was to investigate whether the tumor microenvironment-derived protein S100A8/A9 qualifies as prognostic marker for melanoma patients, also in the setting of immunotherapy.,S100A8/A9 gene and protein expression were analyzed on melanocytic nevi, primary melanomas and metastases using a cDNA library and three independent tissue-microarrays (TMA).,Serum levels of S100A8/A9 were measured using a specific ELISA in two independent cohorts of 354 stage III and stage IV melanoma patients as well as in two independent cohorts of patients treated with the PD-1 antibody pembrolizumab.,cDNA analysis revealed an upregulation of S100A8 and S100A9 gene expression in melanoma metastases compared to primary melanomas.,Significantly higher numbers of infiltrating S100A8/A9 positive cells were found in tissue samples of metastasizing primary melanomas compared to non-metastasizing melanomas (P < .0001) and in melanomas of short-term survivors compared to long-term survivors (P < .0001).,Serum S100A8/A9 levels > 5.5 mg/l were associated with impaired overall survival in two independent cohorts (both P < .0001).,Importantly, patients with serum elevated S100A8/A9 treated with pembrolizumab showed significantly impaired survival compared to patients with lower S100A8/A9 levels (cohort 1: P = .0051; cohort 2: P < .0001).,The tumor microenvironment-associated protein S100A8/A9 serves as a novel prognostic marker for metastasis and survival of metastatic melanoma patients and predicts response to immunotherapy with pembrolizumab.,These data underscore the significance of tumor microenvironment-derived factors as suitable biomarkers for melanoma.
Immune checkpoint inhibitors have improved the prognosis of advanced melanoma.,Although anti-programmed death ligand‐1 (PD‐L1) is a well‐studied biomarker for response to anti-programmed death‐1 PD‐1 therapy in melanoma, its clinical relevance remains unclear.,It has been established that the high expression of indoleamine 2,3‐dioxygenase (IDO) is correlated to a response to anti-CTLA‐4 treatment in melanoma.,However, it is still unknown whether the IDO expression is associated with response to anti-PD‐1 therapy in advanced melanoma.,In addition, acral and mucosal melanomas, which comprise a great proportion of all melanomas in Asians, are genetically different subtypes from cutaneous melanomas; however, they have not been independently analyzed due to their low frequency in Western countries.,To evaluate the association of IDO and PD‐L1 expression with response to anti-PD‐1 antibody in acral and mucosal melanoma patients, we analyzed 32 Japanese patients with acral and mucosal melanomas treated with anti-PD‐1 antibody from the perspective of IDO and PD‐L1 expression levels by immunohistochemistry (IHC).,Multivariate Cox regression models showed that the low expression of IDO in tumors was associated with poor progression‐free survival (HR = 0.33, 95% CI = 0.13‐0.81, P = 0.016), whereas PD‐L1 expression on tumors was not associated with progression‐free survival.,Significantly lower expression of IDO in tumors was found in non-responders compared to responders.,Assessment of the IDO expression could be useful for the identification of suitable candidates for anti-PD‐1 therapy among acral and mucosal melanomas patients.,Further validation study is needed to estimate the clinical utility of our findings.