Targeting Tryptophan Catabolism in Ovarian Cancer to Attenuate Macrophage Infiltration and PD-L1 Expression.

High-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum is the most common type of ovarian cancer and is predicted to be immunogenic because the presence of tumor-infiltrating lymphocytes conveys a better prognosis. However, the efficacy of immunotherapies has been limited because of the immune-suppressed tumor microenvironment (TME). Tumor metabolism and immune-suppressive metabolites directly affect immune cell function through the depletion of nutrients and activation of immune-suppressive transcriptional programs. Tryptophan (TRP) catabolism is a contributor to HGSC disease progression. Two structurally distinct rate-limiting TRP catabolizing enzymes, indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2), evolved separately to catabolize TRP. IDO1/TDO2 are aberrantly expressed in carcinomas and metabolize TRP into the immune-suppressive metabolite kynurenine (KYN), which can engage the aryl hydrocarbon receptor to drive immunosuppressive transcriptional programs. To date, IDO inhibitors tested in clinical trials have had limited efficacy, but those inhibitors did not target TDO2, and we find that HGSC cell lines and clinical outcomes are more dependent on TDO2 than IDO1. To identify inflammatory HGSC cancers with poor prognosis, we stratified patient ascites samples by IL6 status, which correlates with poor prognosis. Metabolomics revealed that IL6-high patient samples had enriched KYN. TDO2 knockdown significantly inhibited HGSC growth and TRP catabolism. The orally available dual IDO1/TDO2 inhibitor, AT-0174, significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins on immune and tumor cells. These studies demonstrate the importance of TDO2 and the therapeutic potential of AT-0174 to overcome an immune-suppressed TME. SIGNIFICANCE: Developing strategies to improve response to chemotherapy is essential to extending disease-free intervals for patients with HGSC of the fallopian tube, ovary, and peritoneum. In this article, we demonstrate that targeting TRP catabolism, particularly with dual inhibition of TDO2 and IDO1, attenuates the immune-suppressive microenvironment and, when combined with chemotherapy, extends survival compared with chemotherapy alone.

Association of Immediate Postpartum Etonogestrel Implant Insertion and Venous Thromboembolism.

OBJECTIVE: To estimate the rate of readmissions for postpartum venous thromboembolism (VTE) during the first 30 days postdelivery between women with and without the immediate postpartum insertion of the etonogestrel contraceptive implant. METHODS: The Nationwide Readmissions Database from 2016 was used to identify women with a singleton delivery, immediate postpartum insertion of the etonogestrel contraceptive implant, and readmission for VTE within 30 days of discharge. Those with a prior history of VTE or anticoagulant therapy were excluded. These women were compared with the number of women readmitted within 30 days for VTE who did not have the contraceptive implant placed during delivery admission. RESULTS: Of 3,387,120 deliveries, 8,369 women underwent etonogestrel contraceptive implant placement during the delivery admission. There was no difference identified in the rate of readmission for VTE between exposed and unexposed women. Of these, seven had received a postpartum etonogestrel contraceptive implant (0.85/1,000; 95% CI 0.22-1.45/1,000 deliveries), compared with 1,192 without an etonogestrel contraceptive implant (0.35/1,000; 95% CI 0.33-0.37/1,000 deliveries); odds ratio (OR) 2.41; 95% CI 0.58-9.89. The rates of diabetes, thrombophilia, systemic lupus erythematosus, and cesarean birth did not differ between groups. Women who underwent etonogestrel contraceptive implant placement were younger and were more likely to have government-sponsored health insurance, a smoking history, hypertension, peripartum infection, or postpartum hemorrhage than women who did not receive an etonogestrel contraceptive implant (P<.001). After adjusting for these confounders, there remained no difference in rates of VTE, adjusted OR 1.81; 95% CI 0.44-7.45. CONCLUSION: The immediate postpartum placement of the etonogestrel contraceptive implant was not associated with an increased rate of VTE; however, our sample size was underpowered to determine no difference.