American Association for Cancer Research
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FIGURE 5 from Targeting Tryptophan Catabolism in Ovarian Cancer to Attenuate Macrophage Infiltration and PD-L1 Expression

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posted on 2024-03-18, 14:20 authored by Lyndsey S. Crump, Jessica L. Floyd, Li-Wei Kuo, Miriam D. Post, Mike Bickerdike, Kathleen O'Neill, Kayla Sompel, Kimberly R. Jordan, Bradley R. Corr, Nicole Marjon, Elizabeth R. Woodruff, Jennifer K. Richer, Benjamin G. Bitler

A dual IDO/TDO2 inhibitor decreases PD-L1 expression. A, mIHC of ID8 tumors (described in Fig. 4) for F4/80 and PD-L1. B, Quantification of F4/80 and/or PD-L1+ cells. C,CD274 (PD-L1) expression in OVCAR3 following knockdown of TDO2, IDO1, AhR. Internal controls, 18S. D, PD-L1 protein expression measured via flow cytometry following knockdown of TDO2, IDO1, AhR in OVCAR3. E, PD-L1 protein expression measured via flow cytometry following exogenous supplementation of KYN (10 µmol/L) in OVCAR3 and COV504 cells. F, PD-L1 expression in TDO2 or IDO inhibitor epacadostat (10 µmol/L), AT-0174 (5 µmol/L), StemRegenin (10 µmol/L) and 680c91 (10 µmol/L) treated OVCAR3 and COV504 cells. Error bars, SEM. Statistical test, unpaired t test.


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U.S. Department of Defense (DOD)

HERA Foundation

Cancer League of Colorado (CLC)



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. 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.