Abstract
Recent studies suggest that programmed death ligand-2 (PD-L2) constitutes an important antitumor immune response. Here, we investigated the relationship between PD-L2 expression and clinicopathological features in diffuse large B-cell lymphoma (DLBCL). Immunohistochemistry showed that positive expression of PD-L2 was observed in 45 of 181 newly diagnosed patients, including 14 cases with expression exclusively on tumor cells (TCs) and 31 cases with the expression on both TCs and immune cells (ICs) in the tumor microenvironment (TME). In 21 recurrent patients, positive expression of PD-L2 was present in six cases, including two cases with expression exclusively on TCs, and four cases with the expression on both TCs and ICs in the TME. Patients with PD-L2 tumor proportion score (TPS) ≥1% exhibited a better ECOG performance status (PS) (ECOG PS score <2, P = 0.041), lower international prognostic index (IPI) score (P < 0.001), and early Ann Arbor stage (Ann Arbor stage I or II, P = 0.010). Similarly, patients with PD-L2 immune proportion score (IPS) ≥1% also exhibited a better ECOG PS (ECOG PS score < 2, P = 0.006) and lower IPI score (P = 0.001). Survival analysis showed that patients with PD-L2 TPS ≥1% exhibited prolonged overall survival (OS) and progression-free survival (PFS). However, survival analysis showed no prognostic significance based on expression of PD-L2 on ICs in the TME. TC PD-L2 expression was significantly associated with OS (P = 0.041) and PFS (P = 0.001). In the multivariate analysis, TC PD-L2 expression was an independent prognostic risk factor for PFS (P = 0.013), but not for OS (P = 0.249). Furthermore, we found that higher TC and IC PD-L2 expression was associated with higher objective response rate (ORR). Moreover, we demonstrated that the expression level of PD-L2 was positively correlated with the expression status of M1 macrophage markers CD86. Our findings highlight PD-L2 as a promising therapeutic target in DLBCL.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with a wide range of clinical manifestations, which accounts for almost 30% of all non-Hodgkin lymphoma cases [1]
The steps were as follows: paraffin sections were heated at 80°C for 10 min and dewaxed in xylene, gradient alcohol dehydration, 10% neutral formalin immersion for 10 min; antigen was repaired in EDTA solution using microwave repair and cooled to room temperature, after 10 min of blocking, Programmed death ligand 2 (PD-L2) was incubated overnight as an antibody; the secondary antibody was incubated for 10 min incubated with fluorescent dye for 10 min, After the microwave repair was cooled to room temperature, the above steps were repeated again to complete the staining of CD68, CD86, and incubated with DAPI for 5 min to stain the nucleus and anti-fluorescence quencher seal
In 181 newly diagnosed patients, positive expression of PD-L2 was observed in 45 cases, including 14 cases with expression exclusively on tumor cells (TCs) and 31 cases with the expression on both TCs and immune cells (ICs) in the tumor microenvironment (TME) (Table 1-1)
Summary
Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with a wide range of clinical manifestations, which accounts for almost 30% of all non-Hodgkin lymphoma cases [1]. Tumor immune escape caused by PD-1 axis may affect the survival time of tumor patients under the inhibitor treatment strategy of non-immune checkpoints. PD-L2 can reflect the degree of immune cell infiltration in follicular lymphoma (FL) and low density of PD-L2 was the most sensitive/specific marker to segregate patients with adverse outcomes [23]. These findings reflect that the expression status of PD-L2 may still affect the clinical efficacy in the absence of PD-1/PD-L1 checkpoint inhibitors, and the prognostic significance of PD-L2 in malignant tumors is still controversial. We used immunohistochemistry to analyze the expression of PD-L2 on tumor cells (TCs) and immune cells (ICs) in the tumor microenvironment (TME) in DLBCL
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