Expression of the Immune Checkpoint Modulator OX40 in Acute Lymphoblastic Leukemia Is Associated with BCR-ABL Positivity

Abstract

OX40 and its ligand are members of the TNF/TNF receptor superfamily, which includes various molecules influencing cellular signaling and function of both tumor and immune cells. The ability of OX40 to promote proliferation and differentiation of activated T cells fueled present attempts to modulate this immune checkpoint to reinforce antitumor immunity. While we recently found evidence for the involvement of OX40 in pathophysiology of acute myeloid leukemia including natural killer (NK) cell immunosurveillance, less is known on its role in acute lymphoblastic leukemia (ALL). In the present study, OX40 expression on ALL cells was significantly associated with positivity for the adverse risk factor BCR-ABL. In line, signaling via OX40 increased metabolic activity of primary ALL cells and resulted in release of cytokines involved in disease pathophysiology. Furthermore, interaction of ALL-expressed OX40 with its cognate ligand on NK cells stimulated ALL cell lysis. The data presented thus not only identify the yet unknown involvement of OX40/OX40L in ALL pathophysiology and NK cell immunosurveillance but also point to the necessity to thoroughly consider the consequences of modulating the OX40/OX40L molecule system beyond its effects on T cells when developing OX40-targeting approaches for cancer immunotherapy.

OX40 and OX40L protein expression of tumor infiltrating lymphocytes in non-small cell lung cancer and its role in clinical outcome and relationships with other immune biomarkers

“…Also, the high or low expression status was related to mutations in AKT/mTOR and Wnt/ β-catenin signaling, respectively. The OX40 expression was also associated with poor prognosis and shorter survival in the study of acute myeloid leukemia (54). In nearly half of the cases, OX40 expression led to proliferation and release of proleukemic cytokines, which provided a survival benefit for leukemic cells.…”

“…To our knowledge, it is the first research to analyze the role of OX40/OX40L in early-stage resectable NSCLC and demonstrate its relationships with PD-1/PD-L1, TILs and patients' clinical outcomes. OX40/OX40L has already been studied previously as an immune characteristic biomarker in some other cancer types, including lymphoma, hepatocellular carcinoma, Leukemia, ovarian, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer and breast cancer (52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). The TILs OX40 was reported to correlate with patient survival.…”

Serum Levels of OX40 in Early and Late-Stage Oral Squamous Cell Carcinoma

“…Xie et al discovered that in hepatocellular carcinoma, the higher OX40 expression in TILs correlated with poor survival [ 14 ]. Similarly, in myeloid leukemia, shorter survival was related to OX40 expression while in patients with an early stage of “non-small cell lung carcinoma” (NSCLC), higher TIL OX40L expression had a poor prognosis [ 15 - 16 ]. On the contrary, lower OX40 expression was correlated with chemosensitivity as well as recurrence-free survival in ovarian cancer patients.…”

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

“…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. Recently, He et al [20] demonstrated that patients in the early stage of NSCLC with a high OX40L expression in TIL had poor prognosis.…”