Original Articles: Translational ResearchCD103 and periplakin are potential biomarkers for response of metastatic melanoma to pembrolizumabEdmonds, Nicole L.a; Flores, Sarah E.a; Mahmutovic, Adelab; Young, Samuel J.c; Mauldin, Ileana S.c,d; Slingluff, Craig L. Jrc,d Author Information aUniversity of Virginia School of Medicine bDepartment of Public Health Sciences, University of Virginia School of Medicine cDepartment of Surgery, University of Virginia Health System dBeirne B. Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, Virginia, USA Received 25 June 2022 Accepted 29 July 2022 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.melanomaresearch.com. Correspondence to Craig L. Slingluff, Jr., MD, Department of Surgery, University of Virginia, Charlottesville, 22901 VA, USA , Tel: +1 434 924 9311; e-mail: [email protected] Melanoma Research: December 2022 - Volume 32 - Issue 6 - p 440-450 doi: 10.1097/CMR.0000000000000855 Buy SDC Metrics Abstract This study was designed to screen for preliminary evidence of predictive markers of melanoma response to PD-1 blockade. We hypothesized that the following immune markers would be positive predictors of response: increased densities of CD103+CD8+ T cells or Th1 lineage T-bet+ T cells, high expression of CXCL9-11 and presence of tertiary lymphoid structures. Conversely, we hypothesized that the high expression of barrier molecules would be a negative predictor of response. Patients with advanced melanoma treated with pembrolizumab were identified, and clinical response as well as overall survival data were collected. Tumor samples were evaluated by multiplex immunofluorescence histology. All statistical analyses were performed in R Studio and Microsoft Excel using the Mann-Whitney U test, chi-square test, Spearman’s rank correlation and Kaplan–Meier survival curves. Sixty-five advanced melanoma patients were identified, of whom 46 met inclusion criteria and were included in this study. Increased densities (P = 0.04) and proportions (P = 0.02) of CD8+ T cells expressing CD103+ were associated with complete response (CR) to pembrolizumab. Improved survival was associated with increased proportions of CD8+ cells expressing CD103 (P = 0.0085) as well as decreased density of periplakin+ cells (P = 0.012) and periplakin+SOX10+ cells (P = 0.0012). The density and proportion of CD8+ T cells expressing CD103+ positively correlated with PD-L1 expression, though PD-L1 expression was not significantly correlated with outcomes. This screening study found that increased density and proportion of CD8+ T cells expressing CD103 and decreased density of periplakin were associated with positive outcomes in patients with melanoma metastases treated with pembrolizumab and may warrant further study. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.