High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients

Abstract

Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early-stage resectable NSCLC remains unclear. We studied gene expression levels of immune-related genes PD-1, PD-L1, PD-L2, IDO-1, IDO-2 and INFγ in tumor tissue of surgically resected NSCLC and correlated the finding with clinicopathological features and patient outcomes. A total of 191 consecutive early-stage NSCLC patients who underwent curative pulmonary resection were studied. The mRNA expression levels of immune-related genes were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Arrays (Qiagen). PD-1, PD-L2 and IDO-2 gene expression levels were significantly higher in patients with squamous histology (p = 0.001, p = 0.021 and p < 0.001; respectively). PD-1, PD-L1 and IDO-2 gene expression levels were significantly higher in patients with higher stage (p = 0.005, p = 0.048 and p = 0.002, respectively). The univariate analysis for recurrence-free survival (RFS) and overall survival (OS) showed that patients with higher levels of three-genes (PD-L1/PD-L2/INFγ) (hazard ratio (HR)) 1.90 (95% confidence interval (CI), 1.13–3.21), p = 0.015) were associated with a worse RFS, while patients with higher levels of both genes (PD-L1/IDO-2) or (PD-L2/IDO-1) were associated with a worse OS (HR 1.63 95% CI, 1.06–2.51, p = 0.024; HR 1.54 95% CI, 1.02–2.33, p = 0.04; respectively). The multivariate interaction model adjusted for histology and stage confirmed that higher levels of three genes (PD-L1/PD-L2/INFγ) were significantly associated with worse RFS (HR 1.98, p = 0.031) and higher levels of both genes (PD-L1/IDO-2) and (PD-L2/IDO-1) with worse OS (HR 1.98, p = 0.042, HR 1.92, p = 0.022). PD-L1/IDO-2 and PD-L2/IDO-1 co-expression high levels are independent negative prognostic factors for survival in early NSCLC. These features may have important implications for future immune-checkpoint therapeutic approaches.

Single-nucleotide polymorphisms and activities of indoleamine 2,3-dioxygenase isoforms, IDO1 and IDO2, in tuberculosis patients

“…IDO-1-mediated tryptophan catabolism is highly conserved in the human response to M. tuberculosis [ 27 ]. However, IDO-1 deficiency fails to impact immune control and infection outcome in the mouse model of TB [ 12 ].…”

The Role of Indoleamine 2, 3-Dioxygenase 1 in Regulating Tumor Microenvironment

“…Although several IDO1 inhibitor monotherapies, including indoximod and epacadostat, have entered phase II trials, it is disappointing that no significant tumor reduction and T cell count changes were observed in preclinical work [ 168 , 169 , 170 ]. The immune checkpoint PD-1/PD-L1 is co-expressed with IDO1 in a range of tumors [ 171 , 172 , 173 , 174 ], and anti-PD-1/PD-L1 and anti-CTLA-4 treatments induce IDO1 expression [ 175 , 176 ], suggesting a possible synergistic relationship may exist between the three. Therefore, an increasing number of clinical trials are now focusing on IDO1 inhibitor combination therapies.…”

Emerging Roles on Immunological Effect of Indoleamine 2,3-Dioxygenase in Liver Injuries

“…These combined observations indicate that IDO1 may have great potential as a marker of prognosis in HCC patients. Interestingly enough, IDO overexpression on tumors may have essential implications for immune-checkpoint therapy (139). It would be ideal for the prediction of patients for the degree of the immune response.…”

“…Interestingly enough, IDO overexpression on tumors may have essential implications for immune-checkpoint therapy ( 139 ). It would be ideal for the prediction of patients for the degree of the immune response.…”

“…The univariate analysis for overall survival (OS) showed that patients of early non-small cell lung cancer with higher levels of both genes (PD-L1/IDO-2) or (PD-L2/IDO-1) were associated with a worse OS. High levels of PD-L1/IDO-2 and PD-L2/IDO-1 co-expression have been independent negative prognostic factors ( 139 ). There are crucial implications of the features of IDO mentioned above for future immune checkpoint therapy ( 140 ).…”