Immune Checkpoint Molecule Indoleamine 2,3-Dioxygenase 1 (IDO1) Is Expressed in Lymphoma Subtypes With and Without Epstein-Barr Virus

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immune regulator involved in innate and acquired immunity and immune escape of tumors. Its expression in the tumor microenvironment of several solid tumors and lymphomas associated with Epstein-Barr virus (EBV), together with the promising results from clinical trials of IDO1 inhibitors, prompted us to evaluate IDO1 expression in a large cohort of 455 lymphomas including 154 cases associated with EBV. We optimized an immunohistochemical assay to evaluate IDO1 staining and show that IDO1 expression in seen in several lymphoma subtypes including classic Hodgkin lymphoma (CHL, 40%), diffuse large B-cell lymphoma (DLBCL, 23.5%), lymphoproliferative disorders in post-transplant settings (LPD-PT, 71.4%), extranodal NK/T-cell lymphoma (ENKTL, 92%), and ALK-negative anaplastic large cell lymphoma (ALCL, 39%), among others. Multiplex immunofluorescence further aided in refining the localization of IDO1 protein expression particularly within the tumor microenvironment. There was a significant correlation between IDO1 expression and EBV positivity in CHL (83.8%), LPD-PT (86.2%), and ENKTL (91.5%), with statistically significant difference in the mean IDO1 H-scores between EBV-positive and EBV-negative cases. IDO1 expression in ALCL was confined to ALK-negative cases with a significant correlation between IDO1 expression and ALK status. Our findings show that IDO1 expression is not only highly correlated with lymphomas associated with EBV, but also found in lymphomas unassociated with EBV, including aggressive and refractory subtypes of lymphomas for which immune checkpoint inhibition through IDO1 could be exploited for therapeutic purposes.