Original ResearchIndoleamine 2,3-dioxygenase 1 and programmed cell death-ligand 1 co-expression correlates with aggressive features in lung adenocarcinoma
Introduction
Lung cancer is a major health burden worldwide and is associated with high mortality [1]. Recent preclinical and clinical studies have considerably increased our understanding of the molecular pathogenesis of lung cancer and have facilitated the development of improved treatment strategies.
Targeting of immune checkpoint factors, such as the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway, has emerged as a novel and promising therapeutic option [2]. Immune checkpoint inhibitors, such as the anti-PD-1 antibodies nivolumab and pembrolizumab and the anti-PD-L1 antibody atezolizumab, have shown survival benefits compared with conventional standard therapy in non-small-cell lung cancer (NSCLC) [3], [4], [5]. However, most patients who initially respond to these inhibitors acquire resistance, and several resistance mechanisms have been identified, including lack of tumour antigens or effective antigen presentation, impaired interferon-γ (IFN-γ) signalling, somatic Janus Kinase 1/2 mutations, impaired immune suppressive cells and/or immunoinhibitory cytokines, upregulation of other immune checkpoints and T-cell exhaustion [6], [7], [8]. Therefore, next generation immunotherapeutic drugs or combinations with cytotoxic chemotherapy and other molecularly targeted therapies should be explored to improve the response rate and to overcome resistance to immune checkpoint inhibitors.
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the rate-limiting step in the kynurenine pathway that catabolizes tryptophan, an essential amino acid critical for cell survival, into a stable metabolite [9]. In the tumour microenvironment, IDO1 is expressed on antigen-presenting cells, such as macrophages, dendritic cells and tumour cells [9], whereas in normal settings, IDO1 is only expressed in tissues with large mucosal surface areas (lungs, gut and placenta) that experience chronic inflammation and lymphoid tissues [9], [10]. IDO1 exerts its immunosuppressive effects in several ways, including induction of T cell dysfunction and apoptosis, promotion of naive T cell differentiation into regulatory T cells and impairment of natural killer cell function through the depletion of tryptophan and generation of kynurenine [11], [12]. Aberrant expression of IDO1 has been shown to correlate with poor clinical outcome in breast, gastric, colorectal and ovarian cancers [13], [14], [15], [16]. However, the clinical significance of IDO1 expression in lung adenocarcinoma has not been fully clarified. Furthermore, the association between IDO1 and immune checkpoint factors, such as PD-L1, remains unclear.
In this translational study, we investigated the association between IDO1 expression and clinicopathological factors and the prognostic value of IDO1 in patients with primary lung adenocarcinoma. We also evaluated the relationship between IDO1 and PD-L1 expression in these tumours. Finally, we examined IDO1 and PD-L1 expression and their modulation by cytokines in lung adenocarcinoma cell lines.
Section snippets
Patients and samples
We performed a retrospective analysis of 427 patients who underwent surgical resection for primary lung adenocarcinoma between January 2003 and December 2012 at the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University. Patients with stage IV disease were excluded. Clinicopathological features, including age at surgery; sex; smoking history; tumour differentiation; pathological tumour, node and metastasis stage (seventh edition of the American Joint Committee
Association between IDO1 expression and clinicopathological factors in patients with primary lung adenocarcinoma
A total of 427 patients with primary lung adenocarcinoma who underwent surgical resection were included in this study (Supplementary Table 1). Of these, 211 (49.4%) were male, and 205 (48.0%) were smokers. The median age was 69 years (range: 29–85). The EGFR mutation status was available for 250 patients, of whom 118 (47.2%) harbored mutant EGFR: 43 (36.4%) with exon 19 deletions, 69 (58.5%) with exon 21 L858R point mutations and 6 (5.1%) with other minor mutations. PD-L1 expression was
Discussion
We detected IDO1 expression in resected lung adenocarcinoma from 60.9% to 14.8% of patients using a cut-off of 1% and 50%, respectively. Previous studies demonstrated that IDO1 was expressed in tumour tissue from 40 to 79% of NSCLC patients [10], [19]. Because immunohistochemical evaluation of IDO1 in lung adenocarcinoma is not well established, we analysed the data based on both 1% and 50% positivity cut-offs. At 1%, the proportion of IDO1-positive tumours in our study was similar to that
Funding statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in association with the present study.
Acknowledgements
The authors thank Anne M. O'Rourke, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
References (42)
- et al.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial
Lancet
(2017) Indoleamine 2,3 dioxygenase and regulation of T cell immunity
Biochem Biophys Res Commun
(2005)- et al.
Clinical significance of PD-L1 protein expression in surgically resected primary lung adenocarcinoma
J Thorac Oncol
(2016) - et al.
Immunohistochemical and image analysis-based study demonstrate that several immune checkpoints are co-expressed in non-small cell lung carcinoma tumors
J Thorac Oncol
(2018) - et al.
PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project
J Thorac Oncol
(2017) - et al.
Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas
Mod Pathol
(2016) - et al.
Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases
J Thorac Oncol
(2010) - et al.
The global burden of cancer 2013
JAMA Oncol
(2015) The blockade of immune checkpoints in cancer immunotherapy
Nat Rev Cancer
(2012)- et al.
Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer
N Engl J Med
(2015)
Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer
N Engl J Med
Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints
Nat Commun
Primary resistance to PD-1 blockade mediated by JAK1/2 mutations
Cancer Discov
Mechanisms of resistance to immune checkpoint inhibitors
Br J Cancer
Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues
Cancer Immunol Res
The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function
Blood
The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells
J Immunol
Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells
Clin Cancer Res
Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer
Br J Cancer
Analysis of indoleamine 2-3 dioxygenase (Ido1) expression in breast cancer tissue by immunohistochemistry
Cancer Immunol Immunother
Increased expression of Ido associates with poor postoperative clinical outcome of patients with gastric adenocarcinoma
Sci Rep
Cited by (34)
Solid-type poorly differentiated adenocarcinoma of the stomach: A characteristic morphology reveals a distinctive immunoregulatory tumor microenvironment
2022, Pathology Research and PracticeCitation Excerpt :The effects of PD-L1/IDO-1 expression and TILs on the prognosis of gastric cancers have been controversial; prior studies have reported that IDO1 as associated with poor prognosis [20,21] whereas high levels of visual TIL estimates and Foxp3+ TILs were markedly associated with increased overall survival [22]. In other malignancies, both PD-L1 expression [23] and IDO1 expression [8–10] have been associated with worse prognosis. For accurate prognosis estimation, it is necessary to categorize a large number of gastric cancer cases both molecularly and morphologically, and then analyze the prognosis for each subtype.
Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma
2020, CellCitation Excerpt :The protein abundance of some important immune evasion markers (Jerby-Arnon et al., 2018), including IDO1, was upregulated in both the HTE and INFG-high clusters (Figures 5A and S5A). IDO1 has well-documented roles in angiogenesis, EMT (Zhang et al., 2019), and cancer immunosuppression (Liu et al., 2018); hence, IDO1 inhibition may represent an additional therapeutic opportunity in immune-hot LUAD tumors (Kozuma et al., 2018; Takada et al., 2019). Other important immune-evasive or immune-related markers were also observed.
Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors
2019, European Journal of Medicinal ChemistryCitation Excerpt :Despite of the recent negative result from a phase III clinical trial (ECHO-301) combining epacadostat with pembrolizumab, which may be attributed to several issues such as the possible structure-related pharmacokinetics limitations, inapplicable pharmacodynamics indicators, unreasonable combination therapy strategy or clinical trial design [15], many IDO1-related clinical trials are still in active state for the treatment of patients with many cancer types [16]. Furthermore, several studies showed that high expression of IDO1 was significantly associated with higher tumor grade, vascular invasion, PD-L1 expression, and adverse clinical outcomes [17–20]. Additionality, in a preclinical anti-PD1-resistant lung adenocarcinoma model, IDO1 inhibition can reactivate antitumor immune responses by blocking IDO1-expressing MDSCs [21].
PD-L1 expression on tumor-infiltrating immune cells is highly associated with M2 TAM and aggressive malignant potential in patients with resected non-small cell lung cancer
2019, Lung CancerCitation Excerpt :Experimental studies have reported that tumor cells can induce M2 macrophages with increased expression of PD-L1 [26,27]. PD-L1 expression is generally considered to be induced at the transcriptional level after exposure to IFN-γ released by T effector cell [28–30]. In fact, it was revealed that PD-L1 induced by IFN-γ from TAMs promoted the progression of lung cancer [31].
Immune evasion in lung metastasis of leiomyosarcoma: upregulation of EPCAM inhibits CD8<sup>+</sup> T cell infiltration
2024, British Journal of Cancer