Association of IDO immune suppression with brain metastasis in non-small cell lung cancer.
Authors: Chen Weiwei , Yang Li , Pang Dazhi , Liuru Taiyang , Liang Zhibing , MA Lingyu , Zhang Fan , Xu Wanli , Zhang Jitian , Luo Min , Zhao Caining , Xu Liangliang , LI Shanshan , Xu Zhiyuan , Kong Feng-Ming Spring 
Published: June 2021

e21215

Background: Indoleamine 2, 3-dioxygenase (IDO), a known immunoinhibitory enzyme, plays an important role on tumor metastasis through manipulation of host immune status. We have demonstrated that IDO level has prognostic value and low IDO level is associated with low risk of distant metastasis in patients with non-small cell lung cancer (NSCLC). However, the association between IDO immune status in patients with brain metastasis (BrM) is unknown. We hypothesized that the IDO1 activity are different in the NSCLC patients of various stages and in patients with or without BrM and the IDO mRNA expression in brain metastatic lesion differ from the primary tumor or metastasized regional lymph nodes. Methods: This was part of a prospective study of blood immune biomarkers for prognosis and prediction. Newly diagnosed or recurrent NSCLC patients were eligible. Blood samples were obtained before treatment start and plasma were used for the Kynurenine (Kyn) and tryptophan (Trp) measurement by the high-performance chromatography. Kyn and trp was detected with more than 95% re-productivity. IDO activity was defined as ratio of kyn/Trp. Student T-test and One-way anova were applied for group comparison. CI: confidence interval. P < 0.05 was considered as statistical significance. The IDO cellular expression was analyzed by the http://ureca-singlecell.kr/ website tool using the GEO dataset GSE131907. Results: Between July 2019 and Dec 2020, a total of 121 patients with NSCLC were eligible. The mean concentration of Kyn was 1.69 uM in patients with stage IV (n = 60, CI: 1.38-2.00), compared with 1.57 in patients with stage I (n = 38, CI: 1.03-2.10), 1.63 in stage II (n = 13, CI: 1.03-2.23) and 2.01 in stage III (n = 10, CI: 0.72-3.30, mean = 2.01). The mean ratio of Kyn:Trp was 0.10 in stage IV (n = 60, CI: 0.07-0.12), compared with 0.13 in patients with stage I (n = 38, CI: 0.06-0.20), 0.15 in stage II (n = 13, CI: 0.03-0.29) and 0.15 in stage III (n = 10, CI: 0.12-0.29). In patients with stage IV, there was no significant difference in the kyn concentration in patients with BrM (n = 13) and those without BrM (n = 47) (mean: 1.74, CI: 0.47-2.41 v.s 2.03 mean: 1.12-3.08; p = 0.45). The IDO activity in the patients with BrM was not significantly different from that of patients without BrM (mean: 0.11, CI: 0.03-0.20 v.s mean: 0.13, CI: 0.08-0.17; p = 0.74). Interestingly, GEO dataset analysis of the IDO1 mRNA expressions in 44 patients showed enrichments in myeloid cells in primary lung cancer tumor, natural killer cells in metastasized lymph nodes, and B cells in brain metastatic lesion. Conclusions: This study demonstrated no significant differences in circulating IDO expressions in patients with brain metastasis but differential IDO patterns of cellular expression in brain metastasis from that of primary tumor in NSCLC patients. This finding suggests the need of new strategy of research for immune status in the brain metastatic process of non-small cell lung cancer.