CD274 Alterations and PD-L1 Expression on Tumor Cells and Tumor-Infiltrating Lymphocytes in Patients With Melanoma: Relationships to Histopathologic Features and Outcomes.

Abstract

In patients with melanoma, the predictive and prognostic relevance of programmed death ligand 1 (PD-L1) protein expression on tumor cells and tumor-infiltrating lymphocytes (TILs) and of alterations in the gene encoding PD-L1, CD274, are not yet established. To address these gaps in knowledge. We retrospectively evaluated 64 patients with melanoma treated with immune checkpoint blockade therapy (ICBT) who underwent whole genome sequencing. PD-L1 immunohistochemistry using clone 28-8 was available for 33 of 64 patients. Tumor cell PD-L1 expression was categorized as negative (<1% of cells staining), low (1%-10%), or high (>10%), and TIL PD-L1 expression as low (≤30% of TILs expressing PD-L1) or high (>30%). Event-free survival (EFS) and overall survival were assessed in relation to genetic and histopathologic factors. CD274 alterations were identified in 19% (12 of 64) of tumors and were associated with higher tumor mutational burden. Of 33 tumors assessed by immunohistochemistry, 21 showed PD-L1 positivity in tumor cells, which correlated with higher N category, reduced microsatellite stability, and elevated BRAF (B-Raf proto-oncogene, serine/threonine kinase) alteration rate. High PD-L1 expression on TILs was linked to more advanced disease and increased lymphovascular invasion. Among patients with similar clinical stage, patients receiving PD-L1-targeted ICBT had better EFS and overall survival than patients receiving non-ICBT or excision. Notably, patients with gene amplifications of undetermined significance identified on whole genome sequencing had reduced EFS. Our findings suggest that CD274 alterations, PD-L1 expression on tumor cells and TILs, BRAF mutations, genomic amplifications, and tumor mutational burden may provide meaningful prognostic information in patients with melanoma. Prospective validation in larger cohorts is warranted to confirm the utility of these markers in guiding therapeutic decisions.