PD-L2 Landscape and Correlation With Outcome: An Immunomic Analysis

PURPOSE PD-L1 and PD-L2 are inhibitory ligands that interact with PD-1 receptors, enabling immune escape. Although PD-L1 has been extensively studied, much less is known about PD-L2. PD-L2 expression could lead to incomplete blockade of the PD-1 axis by anti–PD-L1 agents and also influence the activity of anti–PD-1 agents. METHODS We analyzed PD-L2 transcriptomic expression in a pan-cancer cohort (N = 514; 489 patients with advanced/metastatic disease and clinical correlates available) for associations with immunomodulatory variables and outcome. RESULTS The most common tumors were colorectal (27% 140 of 514), pancreatic (11% 55 of 514), and breast cancer (9.5% 49 of 514). High PD-L2 expression (≥75th RNA percentile rank) occurred in 19.5% (100 of 514) of patients; PD-L2 expression varied across and within tumor types. High PD-L2 independently/significantly correlated with high PD-L1, PD-1, CD4, and T-cell immunoglobulin and mucin-containing protein 3 (TIM-3) RNA levels (both as dichotomized and linear variables), high tumor mutational burden (TMB; ≥10 mutations/Mb), and a breast cancer diagnosis. In 217 patients who received immune checkpoint blockade (mainly anti–PD-1-based regimens), high versus moderate/low PD-L2 predicted longer overall survival (OS) (but not progression-free survival) in univariate analysis (median, 1.88 years 95% CI, 1.37 to not estimable versus 1.21 years 95% CI, 0.95 to 1.54; P = .02). In 272 patients who never received immunotherapy, high PD-L2 expression was not prognostic for OS. CONCLUSION High PD-L2 transcripts were more common in breast cancer and associated with high expression of other immune-relevant factors: PD-L1, PD-1, CD4, and TIM-3, and with TMB ≥10 mutations/Mb. High PD-L2 levels correlated with longer OS in immunotherapy-treated patients.