Indoleamine 2,3-Dioxygenase 2 Immunohistochemical Expression in Resected Human Non-small Cell Lung Cancer: A Potential New Prognostic Tool

Abstract

Indoleamine 2,3-dioxygenase 2 (IDO2) is an analog of the tryptophan degrading and immunomodulating enzyme indoleamine 2,3-dioxygenase 1 (IDO1). Although the role of IDO1 is largely understood, the function of IDO2 is not yet well-elucidated. IDO2 overexpression was documented in some human tumors, but the linkage between IDO2 expression and cancer progression is still unclear, in particular in non-small cell lung cancer (NSCLC). Immunohistochemical expression and cellular localization of IDO2 was evaluated on 191 formalin-fixed and paraffin-embedded resected NSCLC. Correlations between IDO2 expression, clinical-pathological data, tumor-infiltrating lymphocytes (TILs), immunosuppressive tumor molecules (IDO1 and programmed cell death ligand-1 -PD-L1 -) and patients' prognosis were evaluated. IDO2 high expression is strictly related to high PD-L1 level among squamous cell carcinomas group (p = 0.012), to either intratumoral or mixed localization of TILs (p < 0.001) and to adenocarcinoma histotype (p < 0.001). Furthermore, a significant correlation between IDO2 high expression and poor non-small cell lung cancer prognosis was detected (p = 0.011). The current study reaches interesting knowledge about IDO2 in non-small cell lung cancer. The close relationship between IDO2 expression, PD-L1 increased levels, TILs localization and NSCLC poor prognosis, assumed IDO2 as a potential prognostic biomarker to be exploited for optimizing innovative combined therapies with immune checkpoint inhibitors.

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

“…Among these, IDO-1 was evaluated as a further target for immunotherapeutic intervention by the evidence reported in some studies showing its pro-tumorigenic effect [46]. Regarding the expression of IDO-1 and IDO-2, several studies show that their role can influence tumor progression [47]. In particular, the study by Lindström, V, et al showed that increased IDO-1 activity in patients with chronic lymphatic leukemia may affect disease progression [48].…”

Current Challenges for IDO2 as Target in Cancer Immunotherapy

“…More recently, human gastric, colorectal, and renal carcinomas have been found to constitutively express both IDO1 and IDO2 (24), and the same has been observed in brain tumors (25). Interestingly, IDO2 is particularly overexpressed in pancreatic ductal adenocarcinoma (PDAC) (26) and non-small-cell lung cancer (NSCLC) (27).…”

“…In a recent study with 191 NSCLC patients, IDO2 was highly expressed in 84% of samples and its expression was strictly related to high PD-L1 levels (27). Perhaps most importantly, a significant correlation between IDO2 high expression and poor NSCLC prognosis was detected (27). Intriguingly, IDO2 expression was mainly associated with the basolateral side of the tumor cell membrane, and only few cells stained for IDO2 in the cytosol or nucleus.…”

“…The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. (13,24,26,27) Function in tumors Immune escape Not well defined, may be dependent on the genotype (9,14,29)…”

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

“…Other immuneindependent effects caused by PD-L1 include the activation of mTORC1 and Ras/ERK and signaling cascades, with the following sustained growth of melanoma and ovarian cancer cells and enhanced EMT in glioblastoma multiforme, respectively [96,97]. Moreover, Mandarano et al showed a correlation between upregulated IDO2 and PD-L1 levels, which indicates the existence of a link between IDO2 activity and enhanced cancerogenesis in a PD-L1-dependent manner [98]. Besides affecting PD-L1 expression, NAD + contributes to stem cell proliferation and pluripotency [99].…”