Abstract
The immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO1) and the PD-1/PD-L1 axis are potent mechanisms that impede effective anti-tumor immunity in ovarian cancer. However, whether the IDO pathway regulates PD-1 expression in T cells is currently unknown. Here we show that tumoral IDO1 expression led to profound changes in tryptophan, nicotinate/nicotinamide, and purine metabolic pathways in the ovarian tumor microenvironment, and to an increased frequency of PD-1+CD8+ tumor infiltrating T cells. We determined that activation of the aryl hydrocarbon receptor (AHR) by kynurenine induced PD-1 expression, and this effect was significantly abrogated by the AHR antagonist CH223191. Mechanistically, kynurenine alters chromatin accessibility in regulatory regions of T cell inhibitory receptors, allowing AHR to bind to consensus XRE motifs in the promoter region of PD-1. These results enable the design of strategies to target the IDO1 and AHR pathways for enhancing anti-tumor immunity in ovarian cancer.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in the U.S [1]
We evaluated the clinical outcome of 265 patients with highgrade serous ovarian cancers available in The Cancer Genome Atlas (TCGA) stratified by TIL expression and 44 genes (Supplemental Table 1) related to tryptophan catabolism and aryl hydrocarbon receptor (AHR) signaling
These data suggest that the relationship between IDO1 expression and TIL infiltration is critical in shaping EOC patient outcomes
Summary
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in the U.S [1]. Several studies have demonstrated a positive correlation between EOC prognosis and magnitude of tumor-infiltrating effector T lymphocytes (TIL) [4,5,6], the clinical benefit of TILpromoting immunotherapies – such as immune checkpoint inhibitors (ICI), vaccines, and adoptive cell therapy – is limited by the presence of multiple tolerogenic mechanisms within the ovarian tumor microenvironment (TME). IDO1 is a heme enzyme which catabolizes the first and rate-limiting step of tryptophan (Trp) catabolism along the kynurenine pathway (KP) to generate active immunosuppressive metabolites. In EOC patients, elevated IDO1 expression correlated with a lower Trp:Kyn ratio in the ovarian tumor microenvironment [11], reduced CD8+ TIL frequency [12], poor prognosis [13, 14], and suppression of T cell responses [15]. The vital role of targeting IDO1 for effective immunotherapeutic control of established tumors was observed in pre-clinical models by the synergistic effect of IDO1 inhibition and immune checkpoint inhibitors to mediate the rejection of poorly immunogenic tumors, indicating that IDO1 may be a major mechanism of immunotherapy resistance [16]
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