The prognostic significance of immune checkpoint receptor expression in patients with lymphoma: Association with disease status and clinical outcomes

Abstract

Introduction Little is known about the expression of immune checkpoint receptors in the peripheral blood of lymphoma patients. Herein, we assessed the expression of inhibitory checkpoint receptors, including CTLA‐4, PD‐1/PDL‐1, LAG‐3, and TIM‐3 in the peripheral blood of lymphoma patients and its correlation with the clinical outcomes of patients. Therefore, 47 classical Hodgkin lymphoma (cHL), 48 non‐Hodgkin lymphoma patients with diffuse large B‐cell lymphoma (DLBCL) subtype, and 30 healthy controls were recruited. Methods The expression of inhibitory receptors was evaluated using SYBR Green real‐time PCR method. Results CTLA‐4, LAG‐3, and TIM‐3 genes were significantly upregulated in both cHL and DLBCL patients compared to the healthy controls. In addition, the level of these molecules was differentially expressed in cHL and DLBCL patients at different disease phases compared to the healthy controls. The CTLA‐4 gene was highly expressed in newly diagnosed (ND) cHL patients compared to the relapsed ones. Relapsed DLBCL patients had significantly increased LAG‐3 expression compared to patients at remission, as well as ND patients. Regarding cHL patients, high CTLA‐4 expression was correlated with low lactate dehydrogenase level and better performance status, whereas the level of LAG‐3 was significantly elevated in patients with poor performance status. Lower initial PD‐1 expression was associated with improved disease‐free survival in cHL patients. Conclusions Inhibitory immune checkpoint receptors are aberrantly expressed in the peripheral blood of cHL and DLBCL patients in which high LAG‐3 in DLBCL patients and PD‐1/LAG‐3 in cHL patients are associated with relapse occurrence and worse prognosis, respectively.

The immune checkpoint expression in the tumor immune microenvironment of DLBCL: Clinicopathologic features and prognosis

“…After detecting the expression of PD-1 and LAG-3 in DLBCL tissues in 174 patients,we found that PD-1 and LAG-3 were widely expressed in TILs (Figure 1) and were correlated with bone marrow involvement.The expression of LAG-3 was also different at high and low LDH levels (Table 1). Studies have indicated that the expression level of LAG-3 in relapsed DLBCL patients is up-regulated compared with that of newly diagnosed DLBCL patients, and it is related to PS score (23), suggesting that…”

“…After detecting the expression of PD-1 and LAG-3 in DLBCL tissues in 174 patients,we found that PD-1 and LAG-3 were widely expressed in TILs ( Figure 1 ) and were correlated with bone marrow involvement.The expression of LAG-3 was also different at high and low LDH levels ( Table 1 ). Studies have indicated that the expression level of LAG-3 in relapsed DLBCL patients is up-regulated compared with that of newly diagnosed DLBCL patients, and it is related to PS score ( 23 ), suggesting that the high expression of PD-1 and LAG-3 immune checkpoints may be related to the aggressiveness of DLBCL.In addition, we found a correlation between the expression level of PD-1 and LAG-3 protein ( Table 4 ), indicating that there are some cascades between PD-1 and LAG-3 in the co-inhibitory receptor pathway, which jointly maintain immune microenvironment homeostasis.At the same time, under the long-term stimulation of tumor cells, PD-1+LAG-3+T cells further exhaust, and their ability to produce cytokines and cytotoxic particles is greatly reduced ( 24 ). Most importantly, we found that high expression of LAG-3 in TILs was associated with lower survival in DLBCL patients ( Figures 2 , 3 ).…”

T-cell immunoglobulin mucin molecule-3, transformation growth factor β, and chemokine-12 and the prognostic status of diffuse large B-cell lymphoma

“…CXCL12 is a chemokine secreted by osteoclasts, endothelial cells, and epithelial cells of the central nervous system, and is a pro-inflammatory mediator secreted by cancer-related fibroblasts. CXCL12 regulates neoangiogenesis, tumor cell proliferation, and migration of various solid tumors by binding to chemokine 4 (CXCL4)[ 15 ]. Blocking the CXCL12/CXCL4 pathway can enhance tumor T-cell infiltration, reduce regulatory T-cell production, and enhance antitumor activity[ 16 ].…”