High indoleamine 2,3-dioxygenase transcript levels predict better outcome after front-line cancer immunotherapy

Summary Indoleamine 2,3-dioxygenase 1 (IDO1), which catabolizes tryptophan, is a potential target to unlock the immunosuppressive tumor microenvironment. Correlations between IDO1 and immune checkpoint inhibitor (ICI) efficacy remain unclear. Herein, we investigated IDO1 transcript expression across cancers and clinical outcome correlations. High IDO1 transcripts were more frequent in uterine (54.2%) and ovarian cancer (37.2%) but varied between and within malignancies. High IDO1 RNA expression was associated with high expression of PD-L1 (immune checkpoint ligand), CXCL10 (an effector T cell recruitment chemokine), and STAT1 (a component of the JAK-STAT pathway) (all multivariable p < 0.05). PIK3CA and CTCF alterations were more frequent in the high IDO1 group. High IDO1 expression was an independent predictor of progression-free survival (adjusted HR = 0.44, 95% CI 0.20–0.99, p = 0.049) and overall survival (adjusted HR = 0.31, 95% CI 0.11–0.87, p = 0.026) after front-line ICIs. IDO1 expression warrants further exploration as a predictive biomarker for immunotherapy. Moreover, co-expressed immunoregulatory molecules merit exploration for co-targeting.

The RNA expression of the selected immune factors was calculated, and the transcript abundance of these molecules was normalized and compared to the internal reference consisting of 735 tumors spanning 35 histologies.Rank values of each selected factor were determined on a scale of 1 to 100 as previously reported.Rank values were categorized as low [0-24], intermediate , and high [75-100].
Resource S1.The selected immune factors in the tumor microenvironment associated with indoleamine 2,3-deoxygenease and immune checkpoint inhibitors, related to STAR Methods.

Correlation was tested using
(Panel A) Kaplan-Meier curve based on IDO1 and PD-L1 expression, and (Panel B) IDO1 and PD-1 expression.X axis: Time since initiation of immune checkpoint inhibitors (months).Y axis: Probability of progression-free survival.Expression profiles were stratified by rank values into "not high" (0-74) and "high" (75-100) denoted as "+" and "-" respectively."+" in figure labels mean the "high" group and "-" means the "intermediate/low" group.
Table S4.Summary table of progression-free survival results according to IDO1 and either PD-L1 or PD-1 expression in advanced cancer treated with immune checkpoint inhibitors in the first-line setting (N=102), related to Table 3. (Panel A) IDO1 and PD-L1, and (Panel B) IDO1 and PD-1 expression.

Figure S4 .
Figure S4.Overall survival based on IDO1 and either PD-L1 or PD-1 expression in advanced cancer treated with immune checkpoint inhibitors in the first-line setting (N=102), related to Table 2.

Figure S5 .
Figure S5.Progression-free survival based on IDO1 and either PD-L1 or PD-1 expression in advanced cancer treated with immune checkpoint inhibitors in the first-line setting (N=102), related to Table3.

Table S2 .
Clinical characteristics of patients with advanced solid tumors treated with front-line immune checkpoint inhibitors (n = 102) based on IDO1 RNA expression, related to Table1. ).

Table S3 .
Summary table of overall survival results according to IDO1 and either PD-L1 or PD-1 expression in advanced cancer treated with immune checkpoint inhibitors in the first-line setting (N=102), related to