OX40 expression in hepatocellular carcinoma is associated with a distinct immune microenvironment, specific mutation signature, and poor prognosis

Abstract

Immunotherapy's effect against hepatocellular carcinoma (HCC) is hampered by immunosuppressive mechanisms in the tumor microenvironment. We assessed the clinicopathologic and biologic relevance of OX40, a costimulatory molecular expressed by regulatory T cells (Tregs), in HCC. We analyzed the immunohistochemistry data of 316 patients treated at West China Hospital (WCH) and the RNA sequencing data of 370 patients in The Cancer Genome Atlas (TCGA) to determine the clinicopathologic significance of OX40 in HCC. We also assessed associations between OX40 and multiple immune-related markers. Using the TCGA data, we further characterized the transcriptome, immune cell functions, and mutation signature related to OX40. We found that OX40 expression was higher in HCC than in adjacent liver tissue. In the WCH set, 136 (43%) patients had high-OX40 expression, whereas in the TCGA set, 247 (67%) patients had high-OX40 expression as determined by the X-tile program. High-OX40 expression was associated with high serum alpha-fetoprotein level, vascular invasion, and shorter survival. The prognostic significance of OX40 was validated in additional cohorts. OX40 expression was also associated with CD8A, CD68, LAG3, TIM-3, and PD-1 expression. High-OX40 expression tumors were characterized by upregulated cytokines and exhaustion-specific markers. Analysis of the enrichment data of immune cell types indicated that OX40 expression was associated with the functions of macrophages, plasmacytoid dendritic cells, and co-inhibitory T cells. Finally, high-and low-OX40 expressions were associated with mutations in AKT/mTOR and Wnt/β-catenin signaling, respectively. These results indicate that high-OX40 expression represents the activation of multiple immunosuppressive pathways and provide a rationale for the therapeutic targeting OX40 in HCC patients.

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using Multiplex Quantitative Analysis

“…Similar to our result, high expression of LAG-3 predicted poor survival in head and neck squamous cell carcinoma [41], melanoma [37], soft tissue sarcomas [42] and nonsmall cell lung cancer(NSCLC) [40]. On the contrary, other studies in esophageal squamous cell carcinoma [43], breast cancers [39] and NSCLC [44]show the opposite results, and only one study in HCC has showed no prognostic significance [45]. Differences in patient cohorts, disease types, and selection of cutoffs can contribute to the discrepancy.…”

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using Multiplex Quantitative Analysis

“…Similar to our result, high expression of LAG-3 predicted poor survival in head and neck squamous cell carcinoma [41], melanoma [37], soft tissue sarcomas [42] and non-small cell lung cancer (NSCLC) [40]. On the contrary, other studies in esophageal squamous cell carcinoma [43], breast cancers [39] and NSCLC [44] show the opposite results, and only one study in HCC has showed no prognostic signi cance [45]. Differences in patient cohorts, disease types, and selection of cutoffs can contribute to the discrepancy.…”

High Serum OX40 and OX40 Ligand (OX40L) Levels Correlate with Reduced Survival in Patients with Advanced Lung Adenocarcinoma

“…Several studies on OX40 and OX40L in cancer patients have been conducted. Xie et al [23] found that high OX40 expression in TIL hepatocellular carcinoma correlates with poor survival. Rothfelder et al [24] reported that OX40 expression was related to shorter survival in myeloid leukemia.…”