Impact of PD-L Ligands and Indoleamine 2,3-Dioxygenase on Prognosis and Survival of Diffuse Large B-Cell Lymphoma

Background. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin B-cell lymphoma and one of the most chemosensitive malignant diseases. Modern risk-adapted treatment regimens lead to a good control of the disease and high cure rate. However, 30-40% of patients are resistant to standard and salvage chemotherapeutic regimens. New therapeutic methods are needed to improve the outcome. Currently, a lot of studies are aimed to identify the interplay between immune system and tumor for some newly revealed potential biomarkers.

Goals. We assessed the impact of PD-L1/2 and IDO expression on clinical outcome in patients with primary DLBCL.

Methods: 31 untreated patients were included in the study (median age: 48, range: 23-74 years; males: 9, females: 22). 13 patients were diagnosed with I-II stages and 18 patients with III-IV stages of DLBCL. All patients received R-CHOP/CHOP-like regimens as a 1st-line therapy. PD-L1, PD-L2 and IDO mRNA expression levels were analyzed in fresh pre-treatment lymph node biopsies using qRT-PCR.

Results: The overall response rate in the group was 56.4% (22 patients). Five patients had relapses and six patients had refractory disease (follow-up period range: 7-58 months; median duration - 32 months). All patients with refractory disease and three patients with CR/PR had high expression of PD-L ligands. In order to assess the prognostic relevance of PD-L ligands in DLBCL, Kaplan Meier curves were generated. High expression levels of PD-L1 and PD-L2 in tumors were associated with significantly poorer 3-year event free survival (EFS) compared to tumors with low expression (56% vs. 66% and 60% vs .73%, respectively, p<0.05). DLBCL patients with high expression (>0.0006) level of PD-L1 had a significantly higher risk relapse (p=0.03 by Cox` test).

ROC analysis revealed that the high expression (>0.6878) of PD-L2 in tumor is an important marker that increases the relapse rate for DLBCL patients (Se=41.6 %; Sp=100 %; AUC=0.71, p=0.007).

The mRNA expression of indoleamine 2,3-dioxygenase (IDO) was found in 15 cases (48.4%) and further this group was considered as IDO-positive. The presence of IDO expression was significantly associated with advanced stage of disease (p<0.05), ABC subtype and progression of DLBCL (17.4% vs. 4.3%, p<0.05). Patients with the absence of IDO expression (IDO-negative) tended to have a better response to the 1st line chemotherapy comparing to patients with IDO-positive expression. The overall response rate was achieved in 46.6% (7/15) and 68.7% (11/16) of IDO-positive and IDO-negative cases, respectively (p<0.05).

3-year EFS for patients with IDO-positive expression was lower compared to patients with IDO-negative expression (46% vs .70%, p<0.05).

Summary: The obtained results suggest the high level of PD-L ligands are associated with unfavorable prognosis for patients with DLBCL. Positive expression of IDO could be considered as an additional unfavorable risk factor for this group of patients. It may represent a promising therapeutic target for DLBCL patients with resistance to chemotherapy. Further studies on a larger group of patients are required in order to evaluate the impact of PD-L ligands and indoleamine 2,3-dioxygenase on prognosis and survival of Diffuse Large B-cell lymphoma.